Preparation of 13-alkylgona-1, 3, 5 (10), 8, 14-pentaenes



Aug. 24, 1965 G. A. HUGHES ETAL 3,202,686

PREPARATION OF lS-ALKYLGONA-l 5, 5( l0 8 lll-PENTAENES Filed April 27, 1964 ammo OIwO

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QINQJ Il OImOIm ATTORNEY United States Patent @orden Aian Hughes, 615 Larimer-e Ave., and Herehel Smith, 560 Chestnut Lane, both oi Wayne, Pa. Fitted Apr. 27, 1964i, er. No. 362,572 15 Ciaims. (Cl. 261B-397.45)

This application is a continuation-impart of copending application Serial No. 228,384 filed October 4, 1962, which is a continuation of applications Serial No. 57,904, tiled September 23, 1960, now abandoned; Serial No. 91,341, tiled February 24, 1961, now abandoned; Serial No, 137,535, led September l2, 1961, now abandoned; Serial No. 195,600, iiied May 15, 1962now abandoned; and Serial No. 195,557, filed May 16, 1962, now abandoned. y

This invention relates to compositions of matter classi- -ed in the art of chemistry as substituted unsaturatedgenaue derivatives, to intermediates therefor, and to processes for making and using such compositions.

In describing the invention, references will be made in the following specification to the annexed drawings, wherein:

FIGURE 1 illustrates schematically the reaction sequence for preparing -a 13-alkylgona-1,3,5(lO),8,14-pentaene, speciically 13,8 ethyl 3 methoxygona 1,3, 5(1G),8,14 pentaen 17 one `and using said unsaturated gonane to prepare a 13-alkyl-gon-4-ene, specically 13p,l7ct-diethyl-17-hydroxygon-4-en-3-one.

The invention sought to be patented in fa principal composition aspect is described asrresiding in the concept of a gona-1,3,5(),8,14pentaene nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (FIGURE 1, IX).

The tangible embodiments of said principal composition aspect possess 4the use characteristic of exerting vary-` hormone eflects in animal-s as evidenced by pharmacological evaluation `according to standard test procedures including estrogenic `and lipid shifting etiects. Furthermore, said tangible embodiments of said principal composition aspect possess the use characteristic of `being intermediates for the preparation of compositions exerting hormonal eiiects as evidenced by standard test procedures. Compositions prepared from the principal compositions of the invention show estrogenic, .andr-OgeniC, anti-estrogenic, progestationsl, blood lipid effe-cts, and .anabolic actions, salt retention, salt excretion and central nervous system effects. This vnding indicates their usefulness in the treatment of female hypogonadism, amenorrhea, dysmenorrhea, ovulation block 'and contraception, functional uterine bleeding, acne,`

osteoporosis, infertility, pregnancy maintenance, habitual abortion, weight gain and nitrogen retention,` growth stimulation, post operative recovery,.healing of Wounds, and healing lof burns. In particular it has been established that alterations of the natural steroid structure made pos-sible by our discovery result not nierelyina change of degree of hormonal activity but, ,as a result lof .the separation of types of hormona-l activity, alter in an unexpected way its basic nature Vso that .a desirable hormone effect is maximized 'and an undesirable hormone eiect is minimized.

The tangible embodiments of said composition aspect of the invention possess the inherent general physical properties of `being white crystalline solids, are substantially insoluble in water and are generally soluble in polar solvents such as dimethylacetamide. Examination of compounds produced according to the hereinafter described process reveals, upon ultraviolet and infrared spectrographic Ianalysis, sp-ectral data supporting the molecu'lar structures herein set forth. The aforementioned physical characteristics, taken together with the natureV of the starting materials and the mode of synthesis, conrm the structure `of :the compositons sought to be patented. y

The invention sought to be patented, in a principal process of makin-g the compositions aspect, is described .as residing in the concept of the sequence :of reactions including: converting a compound having a S-phenylpent-l-yne nucleus, ring-unsubstituted in at least one position ortho .to the point of chain attachment, by means of .a Mannion-type reaction, to its acetylenic amine derivative; hydrating the acetylenic linkage to form a 3l eto compound; reacting such 3-keto substrate ccmpound with a nucleophilic Z-monovalent alkyl-1,3-dioxocyclopent-an-o compound under Michael condensation conditions to attach the cyclopentano compound through its 2-position carbon -atom to the l-position carbon atom.

l'of the 3-,keto compound; and treatingthe bicyclic triltetone formed i-n the preceding step with an acidic dehydrating agent thereby to effect a double cyclodehydration to form a- 1,3,5(l0),8,14 entadehydro-13-alkylgonane.

, The invention sought to be patented in a second composition aspect is described as residing in the concept of a 2 (6 phenyl 3 oxohexyl) 1,3 cyclopent-anedione nucleus having attached thereto in titel-position .a monovalent polycarbon-alkyl radical (FIGURE 1, VIII). f

The tangible embodiments of said second composition laspect possess the applied use characteristic of being intermediates for the prepara-tion of compositions exerting hormonal effects as evidenced by standard test procedures.

Y The invention sought to :be patented in a third composition aspect is described .as residing in the concept of a compound having a dialkylamino--phenyl-Z-hexyne nucleus (FIGURE 1, IV).

The tangible. embodiments of said third composition aspect possess the use characteristic of being intermedilates for .the preparation of compositions whi-ch possess the use characteristic of exerting hormonal effects with unexpected separation of .activity as evidenced by standard test procedures.

The invention -sought to be patented in a fourth com-V Yaspect possess the use characteristic of being intermediates for the preparation'of compositions which possess the use characteristic `of exerting hormonal eiiects `with unexpected separation of .activity as evidenced by standa-rd test procedures.

The invention sought to be patented in a fifth composition aspect is described as residing in the concept of a compound having .a 6-phenyl-l-hexen-3-one nucleus (FIGURE il, VI).

The tangible embodiments'of :saiditth composition aspect possess the use characteristic of being intermediates for the preparation of compositions which possess the use characteristic of exerting hormonal effects with unexpected separation of activity .as evidenced by standard k.test procedures. p

The invention sought to be patented in assixthV composition aspect is described as residing in the concept of a compound having a 2-polycarbonalkyl-1,3-cyclopentanedione nucleus (FIGURE 1, VII).

The tangibleV embodiments of said sixth composition aspect possess the yuse characteristic of being intermediates for the preparation of compositions which possess the Patented Aug. 24, IESS a use characteristic of exerting hormonal eiiiects with unexpected separation of activity as evidenced by standard test procedures.

The invention sought to be patented in a second process aspect is described as residing in the concept of reacting a compound having a 6-phenyl-1-hexen-3-one nucleus unsubstituted in the l-position (FIGURE 1, VI), or, alternatively, reacting a compound having a 6-phenyl-3- hexanone nucleus to which is attached at the l-position a group which will eliminate with hydrogen under Michael conditions (FIGURE l, V), With a nucleophilic compound having a 1,3-dioxocyclopentano nucleus which has at least one hydrogen in the 2-position, under Michael condensation, to attach the cyclopentano-compound nucleus through its 2-position carbon to the l-position carbon atom of the 3-keto compound nucleus, thereby to form a 2- (6-phenyl-3-oxohexyl) 1,3-cyclopentanedione (FIGURE l, VIII).

The invention sought to be patented in a third process aspect is described as residing in the concept of treating a compound having a 2-(6-phenyl-3-oxohexyl)-l,3cyclo pentanedione nucleus which has an ortho-para directing substituent (FIGURE 1, VIII), with catalytic amounts of a suitable dehydrating acid, such as polyphosphoric or p-toluene sultonic acid, under conditions which result in the removal of water to form a tetracyclic compound (FIGURE l, IX).

The manner and process of making and using the invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same, as follows:

Referring now to FIGURE l, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely 13-ethyl-3-mcthoxygona-1,3,5(10),8,14pentaen 17 one, and the sequence of reactions involved in the use of said unsaturated gonane to prepare a 13-alkylgon4ene, specically, 13;?, 17a-diethyl-17,6-hydroXy-gon-4-en-3one, is illustrated. 3-(m-methoxyphenyl)propanol (I) is heated with phosphorus tribornide in benzene after dropwise addition in the cold to form 3-(rn-methoxyphenyDpropyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(rn-methoxyphenyl)-l-pentyne (III). Compound III is allowed to stand under nitrogen with Water, 30% formalin, acetic acid, diethylamine, dioxane, and cuprous chloride at 7 C. for about l2 houru whereby there is obtained l-diethylamino-6-(rn-inethoxyphenyU-Z-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1diethylamino 6 (ni-methoxyphenyl)-S-hexanone (V). The ketarnine (V) may eliminate diethylamine on distillation to give the vinyl ketone -(m-methoxyphenyD-lheXen-B-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with Z-ethyl-l,3-cyclopentanedione (VII) under Michael con densation conditions, eg. retluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphcnyl) 3-oxohexyl]-l,3cyclopentanedione (VIII).

Compound VIII is then cyclodehydrated at the reilux temperature of a solvent, such as benzene, in the presence of a dehydrating acid, such as p-toluene sulfonie acid, to eiect simultaneous ring closures to give the tetracyclic compound 13,6 ethyl- 3 methoxygona 1,3,5(it`1),8,14 pentaen-17-one (IX). To use said compound the lli-unsaturation .of Compound IX is then selectively hydrogenated in the presence of a metal catalyst, such as 2% palladized calcium carbonate, to form IS-ethyl-S-rnethozrygona 1,3,5 l(l),8 tetraen-17-one (X). Ethynylation at the 17-position of Compound X with lithium acetylide in dimethylacetamide gives l3ethyla17aethynyl 3-methoxygona 1,3,5 (l0),8 tetraen-l7-ol (XI). The ethynyl group of Compound XI is then selectively hydrogenated to ethyl, as in the presence of a supported palladium catalyst, to produce 13p,17a-diethyl-3-methoxygona- 1,3,5 (10),Stetraen17ol (XII), which is then converted to 1B,17adiethyl3-methoxygona-l,3 ,5 lO) -trien-17/3-ol (XIII) by alkali metal reduction in liquid ammonia, to provide the normal gonane configuration of (h-8,1444, 13 exocyclic substituents, namely, trans-anti-trans.

By alkali metal reduction in liquid ammonia in the presence of a proton donor, `such as ethanol (Birch reduction), Compound XIII is converted to l3,l7dietl1yl 3methoXy-gona-2,5(10)-dien-l7-ol (XIV). By hydrolysis in the presense of mineral acid, Compound XIV is thon converted to 13/5,l7a-diethyll7-hydroxygon-4-en-3-one (XV).

While the hereinoefore described processes produce novel and steroidal-like compounds which have an unnatural substituent at the l3-position, it is apparent that the novel and valuable processes of the invention offer a unique feasible route to the corresponding natural steroids if the nucleophilic compound used in the Michael condensation step is Z-methyl-l.3-cyclopentancdione.

rThe aromatic ring of the phenylpropanol (FIGURE l, I) used as the starting material for the preparation of the compositions and initial preparations or^ the invention may have one or more substituents, provided, however, at least one position ortho to the position of propanolchain attachment is unsubstituted so that cyclodehydration to form a cyclic structure can eventually be eliectuated. To activate such ortho position for said subsequent ring closure, a para-directing group (referring to electrophilic aromatic substitution) such as hydroxy, acyloxy, alkoxy, amino, alkylamino, or acylarnino is a necessary substituent on the aromatic ring. The group may be present initially or may be introduced later but before ring closure, either directly or by conversion from a meta-directing group such as nitro. After the tetracyclic structure has been formed, substituents can be introduced into thc aromatic A-ring which are not limited as above; however, if such substituted compound is to undergo a reduction, the group is preferably one not sensitive to reduction. After the A-ring has been reduced, the substituents on said A-ring may be the same as those originally present, or substituents to which they may be converted, such as ketonic oxygen, diaikoxy, alkylenedioxy, alkylenethioxy, and alkylenedithio; or groups introducible by known processes, such as halogen or alkyl. For the pr cesses of the invention and except for the limitations expressed in this specification, variations of the substituents on the A-ring of the fully formed tetracyclic structures, or on the intcrmediates leading thereto, are full equivalents of each other.

The carbon atom to Which the phenyl group of the starting propanol (I) is attached can be substituted, as, for example, with an alkyl group, such as methyl or ethyl. Moreover, this atom, to which the phenyl group is attached in Compound I, need not necessarily be carbon. It can be a hetero atom which would not interfere with subsequent catalytic reductions, as, for example, oxygen or nitrogen. This atom will appear in the tetracyclic structures of the invention in the -position, and it will be apparent, may be, as in the case of the nitrogen, sub stituted with hydrogen or an alkyl group.

The 2-carbon atom of the starting phenyl-propanol (I) can also be substituted, as, for example, with an alkyl group, such as methyl and ethyl, and, as such, be unchanged throughout the subsequent synthesis. In the tetracyclic structures of the invention this carbon atom will appear in the 7position.

For the processes of the invention and except for the limitations expressed in this specication, variations of the B-ring on the fully formed tetracyclic structures, or on the intermediates leading thereto, are full equivalents of each other.

In the Michael reaction step, the 3-keto substrate compound can be a 6-phenyl1-heXen-3one, or alternatively, a 6-phenyl-3-hexanone having attached to the 1position andasse a group which will eliminate with hydrogen to form a, 6-

phenyl-l-hexen-3-one under Michael conditions. Thus, a 3keto compound with a l-dialkylamino substituent or its quaternary salt, a l-halo substituent, or a l-hydroxy substituent will react with the nucleophilic compound to form the Michael product. The nucleophilic compound can be a carbocyclic-l,3dione of varying ring size, as,`for example,a five-rnembered ring, a'sixirnembered ring, etc., ultimately forming aY corresponding five-membered, a sixmembered, etc., D-ring in thetetracyclic structure.` The 1,3-cyclodione may also contain a hetero atom at positions other than position 2, thereby to provide a heterocyclic D-ring in the tetracyclic structure. Acylic nucleophilic compounds can be used in conducting the Michaelnjeaction step and the open-chain of the resulting product thereafter ring-closed to form a cyclic D-ring.

For the processes of the invention, and except for the limitationsexpressed in this specification, variations of the D-ring on the fully formed tetracyclic structure, or on the intermediates leading thereto, are full equivalents of each other.

When the nucleophilic compound-is 2methyll,3cy clopentanedione, the invention provides a unique total synthesis for vnatural steroids: the hydrogens at the S- position, 9-position, and 1ct-position being a, and a, respectively, as in the natural steroids. Thus such valuable therapeutic substances as estrone, estradiol,r and l9-nor- Y testosterone are made available from easily obtainable and relatively simple and inexpensive starting materials.,

Moreover, by varying the group at the Z-position of the nucleophilic Michael condensation reactant, the invention provides a way to produce compounds resembling the natural steroids save atfthe 13-position, Thus, by'varying the substituent at the Z-position of the 1,3-cyclopentanedione, alkyl groups of varying c hain length such as, for example, ethyl, isopropyl, cetyl, etc., may be introduced to form the gonane correspondingly substituted at the 13-position. Further, gonanes may be prepared wherein the Y13-position is substituted with any organic radical. Thus, but without limiting the generality ofthe foregoing, an aralkyl, cycloalkylalkyl, or a polycarbonalkylene bridge bearing a hydr0xy, amino, or alkylaminosubstituent can readily be placed in the l3-position, and from such compounds other variations of the` 13-position substituent can be prepared, as haloalkyls from hydroxyalkyls, or quaternary "salts, amides, alkenyls, etc. from aminoalkyls.

For the processes of the invention and except for the limitations expressed in this specification, variations at the 13-position of the fully formed tetracyclic structures or on the intermediates leading thereto are the full equivalents of the claimed l3-position polycarbon-alkyl substituents, having physiological activity of the sameY type.

In any of the intermediate structures or in the tetracyclic structures of the invention having either an aromatic, partially reduced, or totally reduced A-ring wherein the 17-position, or position corresponding thereto in the e carbonyl; or to alkynylhydroxymethylene by addition of the appropriate alkali metal acetylide in a suitable inert solvent; all in the known manner. The carbonyl group may also be ketalized or thioketalized by treating with thek appropriate alcohol or glycol in a suitable solvent under acidic conditions, as in the presence of an acid such as sulfuric acid, p-toluene sulfonic acid, or boron trifuoride etherate, with heating where necessary, according to the known art.

The specific reactions involved in the processes of the 65 invention will now be considered, as follows, reference being made to the drawings for typifying compounds:

The vinyl ketones (VI) of the invention are prepared by elimination of dialkylamine from the corresponding l dialkylaminoethyl aminoketones (V), obtained by hydration'of the acetylenic linkage in an acetylenic amine (IV). The acetylenic amines (IV) Vcan be themselves prepared by a Mannich reaction from the corresponding acetylene (IH) with formaldehyde and a dialkylamine.v The hydration can be carried out, for example, in aqueous sulfuric acid with mercurio sulfate as a catalyst. The corresponding quaternary salts, which may Valso be used in the subsequent Michael condensation, can beobtained by quaternization of the corresponding acetylenic dialkylaminoethyl compound, followed by hydration, or by quaternization of the ketoamine. The vinyl ketones can be, prepared from these derivatives by the above elimination reaction. Thus the ketoarnine or its quaternary salt can be treated with a base for this purpose, for example, with sodium hydroxide or a sodium alkoxide.

lThe vinyl ketones (VI) and dia-lkylamino ketones (V) yare condensed with `a nucleophilic compound under Michael reaction conditions. Thus, the condensation canbe carried out by bringing the ltwo reagents together in solution in the presence of a base, for example, pyridine,` triethylam-ine, diethylamine, sodium hydroxide, or sodium meth-oxide, and heating as required. The nature and amountv of base employed in the condens-ation reaction will depend upon the particular reagents used. Where the vinyl ketones derivative employed is a keto-amine and dialkylamine is eliminated in the reaction, no added Vbase may be required. Where the compound is a 2-alkylcyclopentane-LfB-dione (VIII), the compound to be condensed with it is preferably a vinyl ketone, and the dione is used in excess of the molecular equivalent quantity. Suitable solvents are hydrocarbons, such as benzene, `and anhydrous alcohols, such as methanol. If the reaction is carried out in benzene under reuxingconditions, water Vformed in the condensation may be azeotroped out of the reaction mixture with a Dean-Stark type trap.

The double cyclodehydration is brought about by dissolving a compound typified by Compound VIII in -benzene containing a catalytic 1amount of p-toluene sulfonic acid and boiling the mixture under aDean- Stark trap until two equivalents of Water have been collected, or alternatively, by treating the same trike-tone with polyphosphoric acid at room temperature or slightly above until ring closure is complete.

The selective hydrogenation of the gona-1,3,5(10),8,14 pentaenes typified by Compound IX is carried out by means of 2% palladized calcium carbonate. As hereinbefore noted, surprisingly, the catalytic hydrogenation results in addition of hydrogen to the lli-double bond in such a Way as to give the natural stereochemical configuration; that is, the hydrogen .adds at 11i-trans to the alkyl at 13.

vSelective reduction of the 14-ethylenic linkage is achieved by use of catalyst-solvent combination which shows adequate selectivity, and stopping the hydrogenation when the theoretical amount of hydrogen has reacted. Solvents showing selectivity in this regard .are the nonprotonic solvents, that is, hydrocarbons and ethers; benzene, toluene, napht'ha, dioxan, dibutyl ether, and di'ethyl ether are examples of .suitable nonprotonic solvents.v On the other hand, proton-icjsolvents such as acetic acidV and ethanol,V

appear to be largely non-selective. Y

It has beenfound that a moderately active Raney nickel catalyst provides good selectivity in a suitable solvent. If a Raney nickel :catalyst of low activity is employed, `the hydrogenation may be too slow Vto be useful; on the other 70 i and emulsions.

carbonate or on charcoal have all been found suitable in this selective hydrogenation.

Saturation `at the 8- or at the 9( 11)-position of the tetracyclic structures must 'oe stereospecific to obtain the natural type of exocyclic substituent configuration as noted supra. Such a sufficiently stereospecific reduction can be in general effected by the action of an alkali metal (sodium, potassium, or lithium) in liquid ammonia to give the normal steroid configuration hydrogen at the respective carbons. Preferably this type of reduction is carried out in the presence of a primary or secondary aromatic amine, for instance aniline, p-toluidine, or diphenylamine, as this can improve the yield :of the desired product. The reduction can also be carried out in the presence of a more reactive proton donor: in this instance, the reduction of the ethylenic linkage occurs with a simultaneous reduction of the aromatic ring to give a 1,4-dihydrophenyl group.

The reduction of 9( 11)-dehydro compounds can also be effected by ca-talytic hydrogenation, as this has been discovered to be sufficiently stereospecitic for production of the desired trans-anti-trans compounds of normal configuration.

While the tetracyclic compounds in this specific-ation and the appended examples are named to describe the configuration corresponding to that of the natural steroids, it is to be understood that unless otherwise indicated, the product of each of the given manipulative procedures is a racemic mixture which contains said named compound and its enantiomorph.

IFor preparing pharmaceutical compounds from the physiologically active compounds of this invention pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, iiavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet-disintegrating agents: it can also be an encapsulating material. In powders the carrier is a nely divided solid which is in admixture with the finely divided compound. In the tablets the compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from or l0 to 99% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, and cocoa butter. The term preparation is intended to include the formulation of the compound with encapsulating material as carrier providing a capsule in which the compound (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used for oral administration.

Liquid form preparations include solutions, suspensions, The compounds are insoluble in water, but can be dissolved in aqueous-organic solvent mixtures that are non-toxic in the amounts used. As an example may be mentioned water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol sol-utions. Aqueous suspensions suitable for oral use can be made by dispensing the finely divided compound in water with viscous material, natural or synthetic gums, resins, etc., for example, gum arabic, ion-exchange resins, methylcellulose, sodium oarboxymethylcellulose and other well known suspending agents.

Preferably the pharmaceutical preparation `is in unit dosage form. In such form, the preparation is sub-divided in unit doses containing appropriate quantities of the cornpound: the 4unit dosage form can be ya packaged preparation, the package containing discrete quantities of preparation, for example, packeted powders of vials or ampules.

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The unit dosage form can be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of compound in a unit dose of prepa-ration may be varied or adjusted lfrom 1 mg. to mg. (generally within the range of 2.5 to 25 mg.) according -to the particular application and the potency of the active ingredient.

The claimed compositions having physiological activity can be incorporated into pharmaceutical formulations including sustained-release agents.

The following preparations illustrate the manner of making the chemical compounds which are the starting materials for use in the processes of the invention.

PREPARATION l.-4,4ETHYLENEDlOXY-4rn NITROPHENYLBUTYRIC ACID GLYCOL MONOESTER Add a solution of 3-(m-nitrobenzoyl)propionic acid g.) (Martin, I. Amer. Chem. Soc., 1936, 58, 1441) in benzene to toluene-p-sulphonic acid (50 g.) and an excess of ethylene glycol. Reflux for 2O hours with removal of Water in a Dean-Stark apparatus. Wash the cooied mixture with water and avaporate the solvent under reduced pressure, to obtain as a gum the crude ethylene glycol monoester of 4,4-ethylenedioxy-4-mnitrophenylbutyric acid.

PREPARATION 2.-4,4ETHYLENEDIOXY 4-m-NITROPHENYLBUTYRIC ACID Mix the ketal ester of Preparation l with an equal Volume of ethanol to make it mobile, and add the solution rapidly to a refluxing solution of sodium hydroxide (50 g.) in water (200 cc.). After 3 minutes cool and pour the mixture into excess dilute acetic acid with shaking. Allow the ketal acid, 4,4-ethylenedioxy-4-m-nitrophenylbutyric acid, to precipitate as a yellow granular powder and filter off g.).

PREPARATION 3.-4m-AMINOPHENYL 4,4-ETHYLENEDIOXYBUTYRIC ACID Shake the nitro ketal acid of Preparation 2 (50 g.) in methanol (500 cc.) withplatinum oxide catalyst (1.5 g.) in hydrogen at atmospheric pressure until hydrogenation ceases (1 hour). Remove the catalyst and evaporate the solvent under reduced pressure to obtain 4-m-aminophenyl-4,4-ethylenedioxybutyric acid as pale yellow fine needles (43 g.).

PREPARArroN 4.- 4-m-N1TROPHENYLBUTYRIC ACID Dissolve amino ketal acid of Preparation 3 (43 g.) in liquid ammonia (1 liter), add sodium (l2 g.) in pieces, and stir the mixture until all the sodium dissolves and the blue color is discharged. Add ammonium chloride (19 g.) to dissolve the precipitate, and more sodium (8 g.). Complete removal of the ketal group is marked by a permanent blue color. Add more ammonium chloride (19 g.), evaporate and extract the solid residue with ethanol. Filter and evaporate, and then extract, filter and evaporate again to obtain crude sodium 4-m-aminophenylbutyrate. Heat on a steam bath for 6 hours at 0.05 mm. pressure to remove most of the ethylene glycol present. Shake the product for several hours in chloroform with toluene-p-sulphonic acid (31 g.), filter the solution, wash the residue with hot chloroform and add the hotchloroform washings to the filtrate. Evaporate the filtrate solvent to obtain crude 4-m-aminophenylbutyric acid as a gum.

Add the crude aminoacid in chloroform (75 cc.) dropwise to a hot solution of peracetic acid in apparatus fitted with a reflux condenser. When the ensuing highly exothermic reaction is complete, pour the chloroform solution into water and then remove the chloroform by steam distillation. On cooling the dark oil obtained partly` solidifies. Crystallize from aqueous methanol, treating 9 with charcoal to remove color, to obtain 4-m-nitrophenylbutyric acid, M.P. 125 C.

C10H1104N Calculated: C, H, 5.3%. C, 57.9%; H, 5.4%.

PREPARATION 5 3-m-NITROPHENYLPROPYL BROMIDE Neutralize the nitroacid of Preparation 4 (9 g.) in ethanol (100 cc.) With N-sodium hydroxide solution. Add a solution of silver nitrate (7.5 g.) in Water (20 cc.) with stirring, and iilter, wash and dry the silver salt at 110 C.; powder the product dry at 100 C. and 0.05 mm. pressure. Suspend the dried silver salt in dry carbon tetrachloride (125 cc.) and add a solution of bromide (6 g.) in carbon tetrachloride. Reflux the mixture for 3 hours, then filter and evaporate; distil the residue to obtain 3-m-nitrophenylpropyl bromide (5 g.), BP. 140 C./ 0.05 mm.

PREPARATION 6.--3m-HYDROXYPHENYL PROPAN- l-OL Add m-hydroxyphenylpropionic acid (57 g.) in dry tetrahydrofuran (250 cc.) dropwise into a vigorously stirred suspension of lithium aluminum hydride (20 g.) in tetrahydrofuran (l liter), at a rate of addition such that gentle retluxing takes place. Reflux the mixture for 6 hours, allow to cool, and stir for 12 hours. Decompose the excess lithium aluminum hydride by careful addition of 50% aqueous ethanol (about 200 cc.), and then add 10% aqueous ethanol (about 200 cc.), and then add 10% aqueous sulfuric acid until the precipitated salts dissolve (ca. 500 cc. acid). Saturate the aqueous layer with salt While stirring, and separate the tetrahydrofuran layer. Wash the resulting aqueous layer with ether. Evaporate the tetrahydrofuran solution under reduced pressure to remove the solvent, take up the residue in ether, and add the other Washings to it. Wash the ether solution with saturated potassium bicarbonate, saturated brine, and nally dry over anhydrous magnesium sulfate. Evaporate the solvent, distill the residue under reduced pressure to obtain a liquid, B.P. 130-2/ 0.2 mm., which crystallizes on standing, forming colorless waxy crystals of 3-m-hydroxyphenylpropan-1-ol (40 g.), M.P. ca. 30.

PREPARATION 7.3m-HYDROXYPHENYL PROPYLBROMIDE Heat and stir the hydroxyphenylpropanol of Preparation 6 (1() g.) with 48% aqueous hydrogen bromide solution (5 cc.) under reflux for 3 hours, then add a further quantity of the aqueous acid (4 cc.) and continue refluxing for 12 hours. Cool, add ether (100 cc.) and Wash the ether solution with water, aqueous potassium bicarbonate, and saturated brine. Dry the solution over anhydrous magnesium sulfate, remove the ether and distill to obtain 3mhydroxyphenylpropyl bromide (10 g), Bl. 1157/ 0.25 mm., as a colorless viscous liquid.

PREPARATION 8 METHYL 3-HYDROXY3-(3 METHOXYPHENYL)BUTANOATE Add m-methoxy acetophenone (100 g.) in benzene (450 cc.) and methyl bromoacetate (153 g.) dropwise to a mixture of acid washed` activated zinc (67 g.), methyl bromoacetate (5 cc.) and a crystal of iodine in benzene ce.) at such a rate that gentle refiuxingtakes place. After the addition is complete continue reiluxing for 1 hour, cool the mixture and pour onto ice and 10% aqueous sulfuric acid. Separate the benzene layer, wash, dry, evaporate the solvent and distil the residue` to give after a' forerun of reactants methyl 3-hydroxy-3-(3-methoxyphenyl)butanoate, B.P. 140/0.65 mm. Hg.

PREPARATlON 9.-METHYL 3-(3METHOXY PHENYL) BUTANOATE Shake methyl 3-hydroxy-3-('S-methoxyphenyl)butanoate (116 g.) in acetic acid (1 liter) with 10% palladized Found l0 charcoal (20l g. of prehydrogenated) in an atmosphere of hydrogen until uptake of hydrogen virtually ceases (12.5 liters of hydrogen absorbed). Filter olf the catalyst, evaporate the solvent and distil the residue to obtain methyl 3-(3-methoxyphenyl)butanoate, B.P. 139-142 at 5 mm. Hg nD25 1.5060, 112.4 g.

Infrared absorption peak at 5.75,u.

PREPARATION 10.--3- S-METHYLPHENYL) BUTAN- l-OL Add methyl 3-(3methoxyphenyl)-butanoate (112 g.)

PREPARATION 1 1.-3 3-METHOXYPHENYL) n-BUTYL BROMIDE Cool 3-(3-methoxyphenyl)butan1ol (84 g.) in benzene cc.) to 0 and add a solution of phosphorus tribromide (55 g.) in benzene (100 cc.) dropwise so that the temperature of the mixture does not rise above 5. Heat the mixture at 60 for 3 hours, cool, pour onto ice, dilute the organic layer with ether and separate it. Wash the organic solution with 3 N aqueous sodium hydroxide, water and dry. Remove the solvent and distil the residue to obtain 3-(3-methoxyphenyl)-n-butyl bromide, 92.8 g., BP. 10U-104 C./0.15 mm.

C11H15OBr Calculated: C, 54.4%; H, 6.23%; Br, 32.85%. `Found: C, 54.48%; H, 6.37%; Br, 32.58%.

infrared absorption peaks at 6.25, 12.66, 11.71p.

To prepare 3-(3-methoxyphenyl)-n-propyl bromide, treat 3-(3-methoxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

Tor prepare '3-(3-ethoxyphenyl)npentyl chloride, reat 3-(S-ethoxyphenyl)pentan-l-ol with a slight stoichiometric excess of phosphorus trichloride according to the manipulative procedure set forth above.

To prepare 3 (3-methoxy-4-ethoxyphenyl)npropyl chloride, treat 3-(B-methoxy-4-ethoxyphenyl)propan-1ol with a slight stoichiometric excess of phosphorus tricliloride according to the manipulative procedure set forth above.

To prepare 3-(3-ethoxyphenyl)-n-butyl bromide, treat 3-(3-ethoxyphenyl)butan-l-ol with a'l slight stoichiometric excess of phosphorus tribromide according tothe manipulative procedure set forth above.

To prepare 3-(3,5-diethoxyphenyl)-n-propyl bromide, treat 3-(3,5diethoxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3-(3-propoxyphenyl)-n-propyl chloride, treat 3-(3propoxypl1enyl)propanl-ol with a slight stoichiometric excess of phosphorus trichloride according to the manipulative procedure set forth above.

To prepare 3- S-propoxyphenyl) -n-butyl bromide, treat 3-(3=propoxyphenyl)butan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare `3(3-methoxy4propoxyphenyl)upropyl chloride, treat 3-(3methoxy4propoxyphenyl)propan-1- ol with a slight stoichiometric excess of phosphorus trichloride according to the manipulative procedure set forth above.

To prepare 3 (3methoxy-4propoxyphenyl)-n-butyl bromide, treat 3(3-methoxy-4-propoxyphenyl)butan1ol i. l with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3-(3-pentyloxyphenyl)-n-propyl bromide, reat 3-(3-pentyloxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3-(3-cyclopentyloxyphenyl)-n-propyl chloride, treat 3-(3-cyclopentyloxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus trichloride according to the manipulative procedure set forth above.

To prepare 3-phenyl-n-propyl bromide, treat 3-phenylpropan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare `3 (3,4 methylenedioxyphenyl)-n-propyl bromide, treat 3(3,ll-methylenedioxyphcnyl)propan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 3-(3,4-dimethoxyphenyl)npropyl bromide, treat 3-(3,4-dimethoxyphenyl)propan-l-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

To prepare 2-methyl-3- 3-rnethoxyphenyl -n-propyl bromide, treat 2methyl3(3-methoxyphenyl)propan1-ol with a slight stoichiometric excess of phosphorus tribromide according to the manipulative procedure set forth above.

PREPARATION 12.-1- (ni-METHOXYPHENYL) 2-BROMOPROPANE Reflux rn-rnethoxyphenylacetic acid (16 g.) with thionyl chloride (35 cc.) for 1 hour. Distil olf the thionyl chloride at atmospheric pressure and the residue at 20 mm. pressure to give m-methoxyphenylacetyl chloride. Add dropwise simultaneously this acid chloride (15 g.) in ether (20 cc.) and a solution of sodium ethoxide (from 5 g. of the metal) in ethanol (80 ce.) to a stirred solution of diethylmalonate (18.5 g.), cooled in an ice bath at such a rate that the temperature does not rise above 5. Pour the solution slowly into dilute sulfuric acid, extract with ether, Wash, dry, evaporate the solvent and reux with a solution of sulfuric acid (48 cc.) in Water (150 cc.) for 4 hours. Extract the cooled solution with ether and remove the solvent from the washed and dried solution to obtain m-methoxyphenyl acetone as an oil. Add this ketone g.) in ether (50 cc.) dropwise to a stirred suspension of lithium aluminum hydride (2 g.)

in ether (60 cc.) and reflux the mixture for 1 hour, then cool and decompose by carefully adding Water. Dissolve the precipitate with 10% sulfuric acid and collect the product in ether. Wash, dry and evaporate the ether solution and distil the residue at mm. to obtain 1-(mmethoxyphenyl)propan-2-ol. Cool this alcohol (8 g.) in benzene (5 ce.) to 0 and add phosphorus tribromide (6 g.) in benzene (5 cc.) dropwise with stirring, keeping the temperature below 5 After the addition is complete, heat the mixture at 60 for 3 hours and pour the cooled solution onto ice and extract the product with ether. Wash the ethereal solution sequentially with dilute aqueous sodium hydroxide, water, dilute hydrochloric acid, and brine, and then dry. Remove the solvent and distil the residue at 20 mm. to give 1(m-methoxyphenyl) 2bromopropane.

PREPARATION 13 .-3- (3 ,5-DIMETHOXYPHENY1.)

n-PROPYL BROMIDE Add phosphorus tribromide (10.7 g.) in benzene (20 cc.) dropwise to 3-(3,5-dimethoxyphenyl)propan-l-ol (16 g.) in benzene cc.) at 0 Keep the mixture at 0 for 1 hour and then heat at 60 for 3 hours. Decompose the cooled solution by adding ice-cold Water. Separate the benzene layer and wash it with dilute aqueous sodium hydroxide, water, dilute hydrochloric acid and then dry.

l2; Remove the solvent and distil the residue at 20 mm. Hg to give 3(3,5-dimethoxyphenyl)-n-propyl bromide.

PREPARATON 14.5 -m-METHOXYPHENYLPEN T- l-YNE Add 3-(3-methoxyphenyl)-npropyl bromide (14 g.) in tetrahydrofuran (15 cc.) with rapid stirring to a solution of sodium acctylide (from 1.84 g. sodium) in liquid ammonia cc.) in a Dewar flask. Continue stirring for 22 hours, then add ammonium chloride (3 g.) and Water (50 cc.). Collect the product with ether and wash and dry the ethereal solution. Distil to obtain 5-m-methoxyphenylpent-l-yne (7.1 gm., 66%), Bl. 7578 C./0.06 mm. Hg.

Cul-i Calculated: C, 82.7%; H, 8.1%. C, 82.2%; H, 7.8%.

To prepare S-m-ethoxyphenylhept-l-yne treat 3-(3-ethoxyphenyl)npentyl chloride with a stoichiometric excess of sodium acctylide according to the manipulative procedure set forth above.

To prepare S-m-propoxyphenylpent-l-yne treat 3-(3- propoxyphenyl)npropyl chloride with a stoichiometric excess of sodium acctylide according to the manipulative procedure set fotrh above.

To prepare 5-m-pentyloxyphenylpent-1yne treat 3-(3- pentyloxyphenyl)-n-propyl bromide with a stoichiometric excess of sodium acctylide according to the manipulative procedure set forth above.

To prepare 5-cyclopentyloxyphenylpent-l-yne treat 3- (3-cyclophentyloxyphenyD-n-propyl chloride with a stoichiometrio excess of sodium acctylide according to the manipulative procedure set forth above.

To prepare 5-m-propoxyphenylhex-l-yne treat 3-(3- propoXyphenyl)-nbutyl bromide with a stoichiometric excess of sodium acctylide according to the manipulative procedure set forth above.

To prepare 5-(3,S-diethoxyphenyl)pent-l-yne treat 3- (3,5diethoxyphenyl)-n-propyl bromide with a stoichiometric excess of sodium acctylide according to the manipulative procedure set forth above.

To prepare 5-(3-methoxy-4-propoxyphenyl)pent-1-yne treat 3(3-methoxy-4-propoxyphenyl) n propyl chloride with a stoichiometric excess of sodium acctylide according to the manipulative procedure set forth above.

To prepare 5-(3-methoxy-4-propoxyphenyl)hex-l-yne treat 3-(3-methoxy-lt-propoxyphenyl) n butyl bromide with a stoichiometric excess of sodium acctylide according to the manipulative procedure set forth above.

Found:

PREPARATION l5 .-5 -PHENYLPENT- l-YNE 43.75 g.) in liquid ammonia (1250 cc.) and allow the ammonia to evaporate. Add 3-phenylpropyl bromide with stirring and continue the stirring for 5 hours while maintaining the reaction mixture at 25-30. Then add ice-water (600 cc.) and extract the mixture thoroughly with ether. Dry the Washed ether solution, evaporate the ether and distil the residue to give 5-phenylpent-1-yne as an oil (121 g.), B.P. 94/50 mm.

CHHlZ Calculated: C, 91.6%; H, 8.4%. Found: C, 91.7%; H, 8.1%.

PREPARATION l6.-5m-NITROPHENYLPENT l-YNE Add 3-(3-nitrophenyl)npropyl bromide (5 g.) to a solution of sodium acctylide (from sodium, 0.48 g.) in liquid ammonia (100 cc.). Stir the dark solution for l2 hours, add excess ammonium chloride, evaporate the ammonia and work up the residue with ether. Distil a portion (2 g.) of the residue to obtain S-m-nitrophenylpent- 1-yne (1.8 g.), B.P. 130 C./0.1 mm.

l E PREPARATION 17.-m-HYDROXYPHENYLPENT l-YNE Pass dry acetylene into stirred liquid ammonia (800 cc.) and add portions of sodium (totaling 10.2 g.) piece by piece as the blue color discharges. When the addition of the sodium is complete, continue to pass acetylene into the `mixture for l5 minutes. Add dimethylformamide (350 cc.) and allow the ammonia to evaporate. To the suspension of sodium acetylide thus obtained, add dropwise 3-(S-hydroxyphenyl)*n-propyl bromide (33.5 g.), and heat the mixture to 60 and maintain at that temperature for 4 hours. Allow to cool, add ice and dilute sulnf uric acid kuntil the aqueousmixture is at pH 6. Extract lthe mixture with ether (a total of 1000 cc.) and wash the extract with saturated brine, concentrate the washed extract to 300 cc., ydry over anhydrous magnesium sulfate, and evaporate olf the remaining ether. Azeotrope the product with benzene to ensure no Vtrace of water remains, to obtain as ,residue a dry oil, crude 5-m-hydroxypheny1- pent-l-yne (about g.).

PREPARATlGN 18.-5-m-ACETOXYPHENYLPENT l-YNE Mix 5-m-hydroxyphenylpent-1yne (about 20 g.) with pyridine (70 cc.) and acetic anhydride (30 cc.) and allow the yhomogeneous mixture to stand for l2 hours at room temperature. Remove excess acetic anhydride by succes sive additions of 95% aqueous ethanol (20 cc.) and evaporation `of the ethyl acetic acetate formed. Remove the remaining solvent and water present by adding benzene and evaporating on a water bath, to obtain a brown oil which on distillation gives S-m-acetoxyphenylpent-l-yne as a pale yellow mobile liquid (24.2 g), BP. 104-8/ 0.1 mm.

Add sodium (4.6 g.) in small pieces to a stirred solution of liquid ammonia (250 cc.) through which a rapid stream of purified acetylene is passed. When the blue coloris discharged, continue the acetylene stream for 15 minutes, and then add dry dimethylformamide (120 cc.), Allow most of the ammonia to evaporate, and then add 3-(3,4-methylenedioxyphenyl)propyl bromide (Preparation 11) (25 g.) slowly, Stir for 3 hours` at 60-70, cool the mixture in ice and decompose by the addition of water (75 cc.) Collect the product in ether and wash with 2 N-sulfuric acid, 2. N-sodium carbonate solution, water and dry. Remove the solvent by evaporation and distil the residue at 0.1 mm. Hg to obtain 5-(3,4methylenedi oxyphenyl)pent1yne.

Infrared (liquid lilm) absorption peaks at 3.06 and 6.25p..

To prepare 5(3,4-dimethoxyphenyl)pent-l-yne treat 3,- (3,4-dimethoxyphenyl)propyl bromide g.) with sodium acetylide acording to the manipulative procedure described above.

To prepare 5-(3,5-dimethoxyphenyl)pent-l-yne treat 3-(3,5-dimethoxyphenyl)propyl bromide (25 g.) with sodium acetylide according to the manipulative procedure described above.

` PREPARATON 20.-5-(3-METHOXYPHENYL) HEX-l-YNE Add sodium (11.5 g.) slowly in small pieces to a stirred solution of liquid ammonia (750 cc.) through which a rapid stream of acetylene is passing at such aV rate that no blue color is formed. Add 3-(3-methoxyphenyl)nbutyl bromide (84 g.) inV tetrahydrofuran rapidly to the well-stirred mixture, and after 22 hours decomposeA the mixture with water, collect the product with ether, wash and `drythe ethereal solution and remove C13H16O YCalculated: C, 83.00%; H, 8.57%. Found: C, 82.79%; H, 8.32%.

lnfrared absorption peaksat 3.06, 4.75, 625g.

i PREPARATION 21.--5`(m-METHOXYPHENYL) 4-METHYL-PENT-l-YNE Add l-(m-rnethoxyphenyl)-2bromopropane (10 g.) to a stirred suspension of magnesium (1.7 g.) in anhydrous ether (40 cc.) containing a crystal of iodine and treat the resulting Grignard solution at0 with 2,3- dibromoprop-l-ene (9 g.) for a period of-1 hour. YReux the mixture for `one hour, cool and decompose with saturated ammoniumv chloride solution. Wash with water and dry the ethereal phase and evaporate the solvent. Dissolve the residue (9` g.) in ether (25 cc.) and add the solution dropwise to a stirred suspension of sodamide (3.5 g.) in liquid ammonia (100 cc.) with external cool- Ving (acetone-Dry Ice bath). Stir the mixture for 2 hours,

`and then allow it to warm upto room temperature. Add ether, and then add saturated aqueous ammonium chloride. Wash.the ethereal solution, dry, evaporate the solution and distil the residue at 0.2 mm., the fraction boiling between 90 and 100 being collected, to obtain 5- (m-methoxyphenly) -4-methylp ent- Lyne.

Infrared absorption peaks at 3.03 and 4.55/r.

Saturate 6-m-methoxyphenylhex-l-en-3fone (1 g.) with dry hydrogen chlorideY gas at 0 C. and keep the mixture at 0 C. for 48 hours. Remove'the excess hydrogen chloride at 0 C. by subjecting theV product to a reduced pressure vof l5 mm. for 30 minutes and then at a pressure of 0.1 mm. for 15 minutes'. The product obtained shows infrared absorption peaks .at 5.87/1, representing a saturated ketone group, and does not give a precipitate with aqueous-ethanolic silver nitrate solution; however, on boiling with aqueous sodium hydroxide followed by acidification with nitric acid and addition of silver nitrate, a copious precipitate of Silver chloride is obtained. This behaviour indicates the product is the expected 1-chloro-6- m-methoxyphenylhexan-3-one.

PREPARATION 23.-1-BROMO-6-m-METHOXY- PHENYLHEXAN-S-ONE Prepare l-bromo-6-m-methoxyphenylhexane-3-one by saturation of 6-methoxyphenylhex-l-en-3-one (1 g.) with dry hydrogen bromide, keeping at 0 for' l2 hours, and

afterwards subjecting the product to a reduced pressure solvent by evaporation. kDistil Vthe residue to obtain 5- of 0.03 mm. for 10 minutes.

The following examples illustrate the manner of using the claimed processes of the invention for the preparation of the claimed compositions of the invention, and for the preparation of natural steroids.

for 12 hours at 70 C. under nitrogen with water (2.5 cc.), trioxan (0.5 gg), 307% formalin (5.5 g.), diethylamine (4.0 g.), acetic acid (2.75 g.), dioxan (25 cc.) and cuprous chloride (0.13 g.). Make the cooled solution alkaline with 10% aqueous sodium hydroxide and extract with ether; then extract the ether extract with 10% Vhydrochloric acid; Wash the acid extract with ether, make alkaline with 10% aqueous sodium hydroxide, extract with ether, Vand then wash and dry theether extract; Distil to obtain 1diethylamino-6-m-methoxyphenylhex-2- yne (10.6 g., 88%), Bl. l30413l C./0.l mm.

C17H25N Calculated: C, 78.7%; H, 9.7%. Found: C, 78.9%; H, 9.6%.

To prepare `1-diethylamino-G-m-ethoxyphenyloct-2-yne treat 5-m-ethoxyphenylhept-lfyne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1diethylamino-6-m-propoxyphenylhex-Z- 15 yne treat S-m-propoxyphenylpent-l-yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1-diethylamino-6-m-pentoxyphenylhex-2- yne treat S-m-pentoxyphenylpent-l-yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1-diethylamino-6-m-cyclopentyloxyphenylhex-2-yne treat 5-m-cyclopentyloxyphenylpent-l-yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1diethylamino-6-m-propoxyphenylhept-2- yne treat S-m-propoxyphenylhex-l-yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare l-diethylamino-6-(3,5-diethoxyphenyl)-hex 2-yne treat 5-(3,5-diethoxyphenyl)pent-l-yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1 diethylamino 6 (3 ethoxy 4- propoxyphenyl)-hex2-yne treat 5-(3-ethoxy-4-propoxy) pent-l-yne (ca. 8 g.) according to the manipulative procedure described above.

To prepare 1 diethylamino 6 (3 ethoxy 4- propoxyphenyl)-hept-Z-yne treat -(3-ethoxy-4-propoxy) hex-l-yne (ca. 8 g.) according to the manipulative procedure described above.

Example 2.-1-diethylamino--plzenyllzex-Z-yne Maintain S-phenylpent-l-yne (20 g.) for 12 hours at 70 under nitrogen with water (6.2 cc.), trioxan (1.2 g.), 30% formalin (13.8 g), diethylamine (10 g.), acetic acid (6.9 g.), dioxan (62 ce.) and cuprous chloride (0.35 gz). Make the cooled solution `alkaline with sodium hydroxide. Extract with ether and extract the ether extract itself with hydrochloric acid. Make the purified aqueous hydrochloric solution thus obtained alkaline again and extract with ether. Dry, evaporate the ether extract and distil the residue to obtain 1-diethlamino-6-phenyl-hex-Z-yne (27.1 g), 13.1). 104-'106/0.2 mrn.

C16H23N Calculated: C. 83.8%; H, 10.1%. 83.9%;1-1, 10.1%.

Prepare l-diethylamino-6-m-nitrophenylhex-Z-yne (1.5 g.), BP. 148% C./0.05 mm., by treating S-m-nitrophenylpent-l-yne (1.8 g.) with Water (0.6 cc.) trioxan (0.1 g.), 30% formalin (1.4 g), diethylamine (1.0 g.), acetic acid (0.7 g), dioxan (6.2 ce.) and cuprous chloride (0.03 g.) according to the manipulative procedure described above.

Found: C.

Example 3 .-1 -d eflzylamno--m-acetoxy phenyl hex-2 -yne Add S-m-acetoxyphenylpent-l-yne (9.5 g.) to a mixture of trioxan (0.5 g.), 40% formalin (5.5 g.), diethylamine (4 g.), acetic acid (2.75 g.), dioxan (25 cc.) and cuprous chloride (0.113 g.), at room temperature. Heat the mixture thus obtained to 70, to obtain a clear green solution, and maintain under nitrogen at that temperature for 12 hours. Cool and add ice, pour the product into ice-cold saturated potassium bicarbonate and extract the mixture with ether. Wash and dry, evaporate the extracts under reduced pressure and distil to obtain l-diethylamino--macetoxyphenylhex-2-yne (9.9 g), B.P. 152-154/ 0.1. mm., as a pale yellow mobile liquid.

Example 4 .-1 -d i etlzy lamno-- (3 ,4f-methyl enedioxypl1enyl)-lzex-2-yne Add 5-(3,li-methylenedioxyphenyl)pent-l-yne (24.5 g.) in dioxan (15 cc.) to a mixture of diethylamine (16 g), trioxan (7.2 g.) and cuprous chloride (0.3 g.) in dioxan ce.) and heat the mixture at 100 for 15 hours under an atmosphere of nitrogen. Filter the cooled solution, remove the solvent and distil the residue at 0.1 mm. Hg to obtain 1-diethylamino-6-(3,4-niethylenedioxyphenyl)-hex-2-yne after a forerun of more volatile material,

Infrared absorption peaks at 6.25, 12.20p.

Heat a mixture of 5-(3-,4-dimethoxyphenyl)-pent-1- yne (8 g.), water (2.5 ce), trioxan (0.5 g), 30% formalin (5.5 g), diethylamine (4.0 g.), acetic acid (2.75 g.), dioxan (25 cc.) and cuprous chloride (0.13 g.) at 70 for 15 hours. Make the cooled solution alkaline with 10% aqueous sodium hydroxide and collect the product. Wash the ethereal solution with water and extract with 10% hydrochloric acid (3x30 cc.). Wash the cornbined aqueous extracts with ether, make it alkaline with 10% sodium hydroxide solution and extract with ether. Wash and dry the etheral solution, evaporate the solvent and distil the residue at 0.1 mm. Hg to obtain l-diethylamino-6-(3,4-dimethoxyphenyl)-hex-Z-yne.

` Infrared absorption peaks at 6.25, 12.20p.

Prepare l-diethylamino-G- 3 5 -dimethoxyphenyl -hex- 2-yne by treating 5-(3,5-dimethoxypl1enyl)-pent-l-yne with Water, trioxan, 30% formalin, diethylamine, acetic acid, dioxan and cuprous chloride according to the manipulative procedure described above.

Example 6.-1-diet/zylamz'n0-6-(3-metl10xyphenyl)- lzept-Z-yne Heat a mixture ot 5 (S-metlloxyphenyl) hex-l-yne (56.6 g), water (17.5 ce), 40% formalin (38.5 cc.), diethylamine (40 cc.), acetic acid (19 cc.), dioxan (1.75 ce.) and cuprous chloride (1 g.) at 70 for 16 hours in an atmosphere of nitrogen. Make the cooled solution alkaline with 10% aqueous sodium hydroxide and extract twice with ether. Wash the ether extracts with Water, ilter and extract with 4 N hydrochloric acid (3 X350 cc.). Make the acid extracts alkaline with 10% aqueous sodium hydroxide, extract with ether and wash the organic solution with water, brine and dry. Evaporate the solvent and distil the residue to Vobtain l-diethylamino-6(S-methoxyphenyl)-hept-2-yne, 79.5 g., B.P. 135-140/0.2 mm. Hg 11D25 1.5116.

CNHMON Calculated: C, 79.07%; Found: C, 78.99%; H, 9.67%.

Example 7.-1-dfeI/zylamllzo-S-metlzyl-t-(m-metlzoxyphenyl) -hex-Z-yne Heat 5- (rn-methoxyphenyl) -4-methyl-pent-1-yne (8 g.), trioxan (0.5 g), 30% formalin (5.5 cc.), diethylamine (4 g), acetic acid (2.75 g), dioxan (25 ce.), and cuprous chloride (0.12 g.) together at for 15 hours. Make cooled solution alkaline with 10% aqueous sodium hydroxide and extract with ether. Wash the ethereal solution with water and extract with 10% hydrochloric acid (3 20 cc.). Combine the acid extracts Wash with ether and make alkaline with 10% aqueous sodium hydroxidegand extract with ether. Wash the ethereal solution, dry, remove the solvent and distil the residue at 0.1 mm. to obtain 1-diethylamino-5--methyl6(m-methoxyphenyl) -l1ex-2-yne.

Example 8.-] -dethylamino--m-methoxyphenylhexavz-- one and d-m-mezhoxyphenylhex-l-en-3-one Add mercurio sulfate (0.45 g.) to a swirled solution of 1-diethylarnino--m-methoxyphenylhex-Z-yne (8.5 g.) in concentrated sulfuric acid (2.5 ce.) and Water (25 cc.). Keep the solution under nitrogen at C. for 1 hour, then cool, make basic with 10% aqueous sodium hydroxide, and rlltcr through glass wool to remove mercuric oxide. Extract product with ether and Wash and dry the ethereal solution. Remove the solvent to obtain the crude ketoamine 1 diethylamino 6-m-methoxyphenylhexan-3- one, infrared `absorption peak at 17l0,u. Distill under reduced pressure with partial elimination of diethylamine, to obtain a mixture of the ketoamine l-diethylamino--mmethoXyphenylhexan-S-one and the vinyl ketone 6-mmethoxyphenylhex-1-en-3-one (7.1 g., ca. 76% B.P. -145 C./0.1 mm.; infrared absorption peaks at 5.85 and 5.95p, the ketoamine predominating.

r lDistil a second portion of the crude ketoaniine l-diethylamino-6-m-methoxyphenylhexan-3-one very slowly over a period of 30 minutes through a Vigreux tractionating column 10 cm. high and 1 inch diameter under reduced pres- After 12 hours wash the mixture With ether to remove un- Y changed reactants and subject to reduced pressure minutes) to remove ether remaining; the residue -is the crude methiodide of the ketoamine (4.6 g.).

Infrared absorption peaks at 5.85 ,tu

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

Example 9.-] -dz'ethylaminO--phenylhexam-S-one and 6- phenylhex-l -en-3-one Add to a solution of 1-diethylamino-6-phenylhex-2-yne (27.1 g.) in concentrated sulfuric acid (7.6 cc.) diluted with wate-r (77 oc.) at 70 mercurio sulfate (1.6 g.), and keep the solution under nitrogen for 1 hour; cool, make basic with sodium hydroxide solution, and lilter through glass wool to remove mercurio oxide. Extract the product with ether .and evaporate the Washed `and dried ethereal solution, leaving crude 1-diethylamino-6-phenylhexan-3- one. Distil under reduced pressure with this ketoamine undergoing partial elimination of diethylamine, to obtain a mixture of the ketoamine, and 6-phenylhex-l-en-3--one (18.9 g.), B.P. 96/0.003 mm.

Infrared absorption peaks at 5.88 and 5.95,u.

To prepare 1- diethylamino-6-m-ethoxyphenyloctan-3 one and 6-m-et-hoxyphenyloct-l-en-3-01'1e, hydrate and distil 1-diethylamino-6-n1-ethoxyphenyloct-2-yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare 1-diethylamino--m-pnopoxyphenylhexan-S one and 6-m-propoxyphenylhex-1-en-3one, hydrate and distil 1-diethylamino-6-m-propoxyphenylhex-Z-yne in the presence of mercury Isalts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-m-pentoxyphenylhexan-3- one and -m-pentoxyphenylhex-1-en-3-one, hydrate `and distil 1diethylamino6-1n-pentoxyphenylhex2-yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare l-diethylamino-6-m-cyclopentyloxyphenylhexan-3 -one and 6-mcyclopentyloxyphenylhex-1en3one, hydrate and distil 1-diethylamino-6-m-cyclopentyloxyphenylhex-2-yne in the presence of mercury salts according to the manipulative procedure set forth above. y

To prepare 1-diethylamino-6-m-propoxyphenylheptan- 3-one `and -m-propoxy'hept-l-en-3-one, hydrate and distil 1diethylamino-6-m-propoxyphenylhept-Z-yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare ldiethylamino6-(3,5diethoxyphenyl)hex an-3-one and 6-(3,5 diethoxyphenyl)*hex-l-en-Ebone, hydrate and distil 1-diethylamino-6-(3,5fdiethoxyphenyl)hex 2-yne in the presence of mercury salts according to the manipulative procedure set forth above.

To prepare l-diethylamino-G-(3-ethoxy 4-propoxyphenyl)hexan3one and 6(3-ethoxy-4-propoxyphenyl) hex-l-en-3-one, hydrate and distil 1-diethy1amino-6-(3- ethoxy 4-propoxyphenyl)hex-2yne in the presence of mercury salts according to the manipulative procedure set forth above. v

These compounds are useful for preparing the novel compositions of this invention which have hormonal activity.

Hydrate 1-diethylamino-6-m-nitrophenylhex-Z-yne (1.5 g.) using the procedure of Example 9 with one twentieth of the quantities of reagents. Remove the solvent to obtain crude 1-diethylarnino--m-nitrophenylhexan-3-one as a clear pale yellow liquid. Distil under reduced pressure, with considerable elimination of diethylamine, to obtain crude 6-m-nitrophenylhex-l-en-3-one (1 g.) as a. clear pale yellow liquid.

Example 1 I .-l-dethylamino-6-111- hydroxy phenylhexan-.-one

Add mercurio sulfate (0.27 g.) rapidly with swirling to a solution of l-diethylamino-6-m-acetoxyphenylhex-Z- yne (3.1 g.) in 10% aqueous sulfuric acid (l5 cc.), and heat the resulting green solution at under nitrogen for 11/2 hours. After cooling, lter to remove mercuri-c sul-` fate and add solid potassium bicarbonate until the product has pH 8.8. Extract the solution with ether. Wash the other extracts with brine made alkaline to pH 8.8, and dry over anhydrous magnesium sulfate. Evaporate the ether at room temperature to obtain as residue crude 1- diethylamino-6-m-hydroxyphenylhexan-3-one asa viscous 'brown oil (2.4 g.) showing infrared absorption at 5.85y. indicating the presence of a keto group, together with the characteristic band of a phenolic hydroxy group and the complete absence of a band at 5.68u corresponding t0 a phenolic acetate group.

This lcompoundis useful for preparing the novel compositions of this invention which have hormonal activity.

Exam ple 1.2.-1 -dz'etlzylamno--m-acetoxyphenylhexane 3-0ne and -m-acetoxypltenylhex-I-en--one Acetylate the crude ldiethy1arnino-6-mhydroxyphenyl hexan-3-one (2.4 g.) by adding pyridine (7 cc.) and acetic anhydride (3 cc.) and allow the mixture to stand overnight at room temperature. Work up the mixture as in the acetylation stage described in the preparation of 5m acetoxyphenylpent-l-yne above, to obtain crude 1-die-thyl amino-6m-acetoxyphenylhexan-3-one -as a viscous brown oil (2.7 g.).

Infrared absorption peaks at 5.68,u. with a shoulder at 585e and no appreciable'phenolic absorption.

LDistil in a Hickman still at 0.1 mm., with partial elimlination of die-thylarnine, and collect a colorlessrmobile liquid, B P. l60-70/ 0.1 mm., which is a mixture (1.8 g.) of the ketoamine and 6-m-acetoxyphenylhex-1-en-3-one.

Infrared absorption peaks at 5.68, 5.88, 5.95/i, the nature vof the absorption indicating a predominance of the vinyl ketone in the mixture.

These compounds are useful for preparing the novel compositions of this invention which have hormonal activity.

ExampleV 13.-1-detlzylamino-6-(3,4- dihydroxypltenyl)hexan-S-one Add mercurio sulfate (0.27 g.) to a swirled solution of 1 diethylamino 6 (3,4 me-thylenedioxyphenylhex 2-yne) (3 g.) in 10% aqueous sulfuric acid (15 cc.) and heat the mix-ture for minutes at 75 in an atmosphere `of nitrogen. `Filter the cooled reaction mixture and addV solid potassium carbonate to pH 8.5. Extract the productV with ether, wash and -dry and evaporate the solvent to leave as residue crude l-diethylamino-6-(3,4-dihydroxyphenyl)hexan3one.

Infrared absorption peaks at 5.85. This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

Exam ple 1 4 .-1 -d iezhy lamino-6 (3,4-dmethoxy phenyl hexan-S-one and 6- (3 ,af-dmellzoxy phenyl hex-1 -en-3- one Add mercurio sulfate (0.45 g. to a stirred solution of 1l diethylamino-6-(3,4-dimethoxyphenyl)hex-2-yne (8.5 g.)`

inV concentrated sulfuric acid (2.5 cc.) and water (25 cc.) and maintain the solution at 75 for 90 minutes. Make the cooled solution basic with 10% aqueous sodium hydoxide and filter to remove mercuric oxide. Extract the product with ether and wash and dry the ethereal solution. Evaporate the solvent to obtain 1diethylamino6(3,4-dimethoxyphenyl)hexan-S-one as an oily residue.

Infrared absorption peaks (liquid film) 5.85/2.

Slowly distil through a short fractionating column at 0.1 mm. Hg to obtain mainly the eliminated product 6- (3,4-dimethoxyphenyl)hex-1-en-3-one.

Infrared absorption peaks (liquid lm) 5.95p..

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

Example 1 5 .-1 -dietlzylam in0-6- 3 ,5 -dimethoxy phenyl l1exan30ne and 6- (3 ,5 -dz'methoxy phenyl hex-1 -en-3-0ne Proceed exactly as described for the preparation of the 3,4-dimethoxy compound above, using 6(3,5dimethoxy phenyl)-1-diethylaminohex-2-yne (8.5 g.), mercuric sulfate (0.45 g.), and 10% sulfuric acid (25 cc.) to obtain 1diethylamino6(3,5-dimethoxyphenyl)hexan-S-one and 6-(3,5dimethoxyphenyl)hex-l-en-3-one.

Example 1 6 .-1 -detl1ylam 1710-6- m-metlioxy phenyl heptan-S-one and 6-(m-metl1oxyphenyl kept-1 -en-S-one Dissolve l-diethylamino-G-(m-methoxyphenyl)hept2 yne (13.6 g.) in 10% aqueous sulfuric acid (40 cc.) and stir with mercurio sulfate (0.69 g.) for 2 hours at 70. Filter the cooled solution, make basic with 10% aqueous sodium hydroxide and extract with ether. Wash the ethereal solution with water and brine, and dry (Na2SO4). Evaporate the solvent and distil the residue to obtain l-diethylamino-6-(m-methoxyphenyl)heptan-3-one which has partially eliminated to 6-(m-methoxyphenyl)hept1-en-3- one during the distillation, B.P. 145 12 mm. Hg.

Infrared absorption peaks at 5.95u.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

Add mercurio sulfate (0.45 g.) to a stirred solution of 1 diethyla-mino 5 methyl 6 (m methoxyphenyl) hex-2-yne (8 g.) in concentrated sulfuric acid (2.5 cc.) and water (25 cc.) and heat the mixture at 70 for 11/2 hours. Filter the cooled solution, make basic with 10% aqueous sodium hydroxide and extract with ether. Wash and dry the ethereal solution and evaporate to leave as residue crude 1diethylamino6(mmethoxyphenyl)5 methylhexan-S-one; infrared absorption peaks at 5.85p. Slowly distil at 0.1 mm. Hg to obtain 5-methyl-6-(mmethoxyphenyl)hex-1-en-3-one; infrared absorption peaks at 5.85,:1.. K

This compound is useful for preparing the novelV compositions of this invention which have hormonal activity.

Example I 8.-6 (m-methoxyphenyl) hex-1 -en-S-one Add mercunic sulfate (1.12 g.) to a swirled solution of 1-diethylamino--(m-methoxyphenyl)hex-2-yne (2.5 g.) in concentrated sulfuric acid (6.25 g.) and water (62 cc.). Maintain the solution at 75 C. for 2 hours, then cool, iilter, make basic and extract with ether. After the solvent has 'been removed, distil the residue slowly over a period of 30 minutes through a Vigreux fractionating column of height 10 cm. and diameter 1 cm. under reduced pressure, to obtain the crude vinyl ketone (14.5 g., B.P. 115-123 C./0.05 mm.) containing a very small amount of ketoamine.

To obtain the pure vinyl ketone, dissolve the distillate (5.2 g.) in ether, wash the solution with dilute hydrochloric acid, followed by Water and sodium bicarbonate solution, dry, and evaporate the ether and redistil the residue. The pure vinyl ketone, -(m-methoxypheuyl) 20 hex-l-en-B-one (B P. 1fl6.8 C./ 0.5 mm.), shows infrared absorption peak at 5.97,u.

C13H16O2 Calculated: C, 76.4%; H, 7.9%. C, 76.3%, H, 8.0%.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

Found:

Example 1 9.-1 -dethylamino-6-m-m ethoxyphenylhexan- 30ne methodde Dissolve 2-ethylcycl0pentane-l,3,4trione hydrate (30 g., M.P. 65-69, Koenigs and Hopmann, Ber., 1921, 54, 1343) in ethanol (200 cc.) and Water cc.). To this solution add dropwise during 1 hour a solution of semicanbazide hydrochloride (21 g.) and sodium acetate (28.2 g.) in water (1200 cc.) with vigorous stirring throughout. Filter off the semicarbazone precipitated wash with meth- `onal, and purify by stirring in reiluxing methanol; lter to obtain a pale cream powder, M.P. 179-182.

Dissolve the semicarbazone (34 g.) in a solution of potassium hydroxide (34 g.) in dry ethylene glycol at and heat the mixture to 160 for 1 hour, followed by 30 minutes at 180. Distil the glycol at 0.01 mm., dissolve the residual solid in water cc.) and make the solution acid .to Congo Red with hydrochloric acid. Cool to 0 overnight and filter. Recrystallize the residue from Water to obtain 2ethylcyclopentane1,3-dione (10 g.), M.P. 180 with sublimation.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

Condense methyl n-butyl ketone with diethyl oxala-te un the presence of sodium ethoxide, and convent the gly- -oxylate obtained Iby heating with hydrochloric acid to 2npropy1cyclopentane1,3,5-trione, from which prepare the .semicarbazonq M.P. 285-289D (decomp.) using semrcarbazide hydrochloride and sodium acetate. Heat the semicarbazone with potassium hydroxide in ethylene gl7y5ccol -to obtain 2-n-propylcyclopentane-1,3-dione, M.P. This c-ompound is useful for preparing the novel compositions of this invention which have hormonal activity.

Example 22.-2-is0propylcyclopentane-l,S-done Add methyl isobutyl ketone (50 g.) and diethyl oxalate g.) to an ice-cold solution of sodium (23 g.) in dry ethanol (350 cc.) with eii'icient stirring, and then reilux the mixture for 30 minutes, cool in ice and quickly add aqueous sulfuric acid (50%, 55 cc.). After 15 minutes iilter off sodium sulfate, wash with ethanol and add the washings to the filtrate; next evaporate to dryness under reduced pressure to obtain ethyl 4-isopropyl2,3,5 trioxocyclopentylglyoxa'late as an uncrystallizable oil. Boil this oil with 2 N hydrochloric acid (1500 cc.) for 1 hour and decant the hot solution from residual tarry material. Filter off the crystals which precipitate from the cooled decanted solution and recrystallize from aqueous ethanol as 2-isopropylcyclopentane-1,3,5-tone, M.P. l09-112.

Treat the trione thus obtained (25 g.) by a procedure analogous `to that described for the corresponding 2-ethyl compound to obtain 2-isopropylcyclopentane#l,3-dione (8.9 g.), M.P. 146.

To prepare 2-(2-hydroxyethyl)cyclopentane-1,3dione 21 treat 4oxopentan1ol with diethyl oxalate, then subject to acid hydrolysis and treat the triene so obtained by the procedure described for the above isopropyl compound.

To prepare 2-(dimethylaminopropyl)cyclopentane-1,3- dione treat 1-dimethylamino-hexan-S-one with diethyl oxalate, then subject to acid hydrolysis and treat the trione so obtained by the procedure described for the above isopropyl compound.

To prepare 2-(2-hydroxypropyl)cyclopentane-l,3dione treat 2-hydroxyhexan-5-one With diethyl oxalate, then subject to acid hydrolysis and treat the trione so obtained by the procedure described for the above isopropyl compound.

To prepare 2-phenethylcyclopentane-1,3-dione treat 1- phenyl-pentan-4-one with diethyl oxalate, then subject to acid hydrolysis and treat the trione so obtained by the` procedure described for the above isopropyl compound.

To prepare 2-isopentylcyclopentane-1,3-dione treat 2- methyl-heptan-6-one with diethyl oxalate, then subject to acid hydrolysis and treat the trione so obtained by the procedure described for the above isopropyl compound.

These compounds are useful for preparing the novel compositions of this invention which have hormonal activity.

Example 23 .-2-11-butylcyclopentane-I ,3-dz'one Condense methyl n-pentyl ketone with diethyl oxalate in the presence of sodium ethoxide, and convert the glyoxylate obtained by heating with hydrochloric acid to Z-n-butylcyclopentane-l,3,5-trione, from which prepare the semicarbazone, M.P. 285-290' (decomp.) using semicarbazide hydrochloride and sodium acetate. Heat the semicarbazone with potassium hydroxide in ethylene glycol to obtain 2-n-butylcyclopentane-1,3-dione, M.P. 149-151.

This compoundis useful for preparing the novel compositions of this invention which have hormonal activity.

Example 24.-Z-sobutyl1,3-cyclopentanedone Add methyl isoamyl ketone (228.4 g.) and diethyl oxalate (644.1 g.) to an ice-cold solution ofsodium methoxide (224 g.) in dry ethanol (1400 cc.) with vigorous stirring and reflux the mixture for 11/2 hours, cool in ice water and then add aqueous sulfuric acid (202 cc. conc. sulfuric acid; 1460 cc. H2O). After relluxing for 11/2 hours, cool the reaction mixture containing 2-isobutylcyclopentane-1,3,5trione to 25 and treat with aqueous sodium hydroxide (50%; 585 cc.). fate precipitate and Wash with methanol (800 cc.). Add the Washings to the filtrate Vand adjust the pH of the resulting solution to 4.5 by adding glacial acetic acid (96 cc.). To this solution add dropwise and with stirring over a period of 40 minute a solution of semicarbazide hydrochloride (223 g.) and sodium `acetate (196 g.) in water (860 cc.). Filter. off the precipitate, wash with Water (3 380 cc.). methanol (3X380 ml.) and dry, t0 obtain 3-isobutyl-1,2,4-cyclopentane-trione-1-semicarba- Zone (184 g., 40.8%); M.P. 277.

Add the semicarbazone (184 g.) to a solution ofsodium methoxide (140 g.) in decanol (817 cc.) `at 120 during 30 minutes and slowly raise the temperature to 200 to remove volatiles boiling below this temperature and then maintain lbetween 20S-215 for 3 hours.` After lowering the temperature to 80, add water 820 cc.) and stir the mixture until the solids dissolve. Adjust the pH of the mixture to 8 by adding aqueous hydrochloric acid and separate the two layers. Extract Vthe decanol layer with 2 portions (each 150 cc.) of water and wash the combined Water layers with toluene. Make the aqueous solution acid to Congo Red With hydrochloric acid, cool to 10, filter and dry the product,'to obtain 2-isobutyl-1,3-cyclopentanedione (113.6 g., 90.6%); M.P. 194-196" after crystallization from ethanol.

Cgi-i140 Calculated: C, 70.02%; H, 9.15%. C, 70.31%; H, 9.25%.

Found:

Filter off sodium sul-V This compound is useful for preparing the novel compositions of this invention which have hormonal activity;

, Example 25.-2-cetylcyclopentane-l,S-done Condense methyl n-heptadecyl ketone with diethy oxalate in the presence of sodium ethoxide to give ethyl 4- cetyl-2,3,S-trioxo-cyclopentyl glyoxylate, which is isolated and recrystallized from hexane, M.P. 69. Reflux this ester with concentrated hydrochloric acid to obtain 2- cetylcyclopentane-1,3,5-trione monohydrate, M.P. 97 102, from which prepare the semicarbazone, M.P. 261 (decomp.) using semicarbazide hydrochloride and sodium acetate. Heat the semicarbazone with potassium hydroxide in ethylene glycol to obtain 2-cetylcyclopentane-1,3-dione, M.P. 12S-130, on recrystallization from chloroform.

This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

Example 26.-2-diethylamnoethylcyclopentaneel, i-diane Dissolve sodium (11.5 g.) in absolute alcohol (175 mL), cool to `0" C., and add a solution of ethyl oxalate (80.0 g.) and S-diethylaminopentanone-Z (38.0 g.) while stirring during 9%; hour. After the reaction mixture is stirred another hour, reux for 30v minutes followed by cooling tok 5 C. Acidify the reaction mixture with HC1 gas and after separating from NaCl, evaporate to dryness `(86.0 g.) Reflux the ester with 2N HC1 (500 ml.) for 1 hour and evaporate the reaction mixture to approximately 100 ml. After neutralizing with NaHCO3, extract the reaction mixture with CHC13 in a continuous extractor. Dry the original layer over Na2SO4 and remove the solvent. Dissolve the residue (21.1 g.) in water (500 ml.) and adjust the pH of the resulting solution to 7 by addition of 2N hydrochloric acid. Extract the solution with chloroform. Dry the organic layer, filter and remove the chloroform by distillation. Distil the product of 0.01 mm., MP. C.

CMHIQNOZ V Calculated: C, 66.97%; H, 9.71%; N, 7.10%. Found: C, 66.76%; H, 10.35%; N, 6.91%.

, This compoundy is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

Reliux a mixture (9 of 1 diethylamino 6 Vmmethoxyphenyl hexan 3 one and 6 m methoxyphenylhex 1 en 3 one with 2 methylcyclohexane- 1,3-dione (4 g.) in benzene (44 cc.) containing pyridine To a mixture of 1-chloro-6-(m-methoxyphenyl)hexan 3-one (0.625 g.), 2 methylcyclohexane 1,3 dione (0.47 g.) and tert-butyl alcohol (0.06 cc.) slowly add triethylamine (0.4 cc.). Heat the mixture at 60 C. for 10 minutes, cool and add ether, wash the solution with dilute sulfuric acid; followed by ammonium sulfate solution and dry; evaporate to obtain the Michael adduct 2 (6 m methoxyphenyl 3` oxohexyl) 2 methylcyclohexane-1,3dione as a gum.

This compound is useful'as an intermediate for preparing the novel compositions of this invention having hormonal activity.

Add to the crude undistilled ketioamine 1-diethylamino- -(m-methoxyphenyl)hexan-3-one (2.3 g), the material obtained by hydration of the acetylenic amine, 2-methylcyclohexanel,3dione (1 g), pyridine (1 cc.) and benzene (12 cc.) and reflux the mixture for 15 hours. Cool the mixture and lter olf unreacted dione, add a little ether to the filtrate, and Wash the ethereal solution with acid, and then Water, and dry. Evaporate the solvents to obtain as residue crude 2(6-m-methoxyphenyl3-oxohexyl)-2-methylcyclohexane-1,3-dione (1.7 g.).

This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

` Example 30.-2(-m-methoxyphenyl-S-oxolzexyl)-2- methylcycIopentane-I,3-dione Reflux a mixture (6 g.) of 1-diethylamino-6-m-methoxyphenlhexan-S-one and 6-m-methoxyphenylhex-1-en-3- 'one with 2rnethylcyclopentane1,3-dione (2.8 g.) in 0.12% dry methanolic postassium hydroxide solution cc.) for 12 hours. Remove most of the methanol under reduced pressure and add a mixture (50 cc.) of equal volumes of benzene and ether; wash the solution with water, alkali and hydrochloric acid, and dry. Evapo- 'rate the solvent to obtain the adduct, the triketone 2-(6- 'an-methoxyplie'nyl-S-oxophexyl)-2methylcyclopentane1, 3-dione (6.7 g.), a viscous brown gum.

To prepare 2(-m-methoxyphenyl-S-oxohexyl)-2-nbutylcyclopentane-l,3-dione, treat a mixture of 1-diethylamino-G-m-methoxyphenylhexan-3-one and 6 m methoxyphenylhex-l-en-3-one with 2-butylcyc1opentane-1,3 dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above. To prepare 2-(6-m-methoxyphenyl-3-oxohexyl)-2-hydroxypropyl-cyclopentane-1,3-dione, treat a mixture of 1- diethylamino6-m-methoxyphenylhexan-3-one and 6-mmethoxyphenylhex-l-en-3-one with 2hydroxypropylcyclo pentane-1,3dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2-(6-m-ethoxyphenyl-3-oxohexyl)-Z-ethylcyclopentane-1,3-dione, treat a mixture of l-diethylamino- 6-m-ethoxyphenylhexan-3-one and 6-m-ethoxypheny1hexv1-en-3-one with 2ethylcyclopentane1,3-dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2 (6 m-propoxyphenyl-3-oxohexyl)-2- phenethylcyclopentane-1,3-dione, treat a mixture of 1- diethylamino-6-m-propoxyphenyl-hexan-3-one and 6-mpropoxyphenylhex-1en3one with 2-phenethylcyclopentane-1,3-dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2-(6-m-pentyloxyphenyl-3-oxohexyl)-2-isobutylcyclopentane-1,3-dione, treat a mixture of l-diethylamino-6-m-pentyloxyphenylhexan-3-one and 6-m-pentyloxyphenylhex-1-en-3-one with 2-isobutylcyclopentane-1,3- dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2-(-m-cyclopentyloxyphenyl-3-oxohexyl) 2-hydroxypropylcyclopentane-1,3-dione, treat a mixture of 1diethylamino6-m-cyclopentyloxyphenylhexan-3-one and 6-mcyclopentyloxyphenylhex-1-en-3-one with 2-hydroxypropylcyclopentane-l,3-dione and dry methanolic potassium hydroxide solution .according to the manipulative procedure described above.

To prepare 2 (6 m-hydroxyphenyl 3 oxohexyl)2- phenethylcyclopentane-l,3-dione, treat a mixture of ldiethylamino-6-m-hydroxypheny1hexan-3-one and 6-mhydroxyphenylhex-1-en-3-one with Z-phenethylcyclopentane-1,3-dione and dry methanolic potassium hydroxide 2li A solution according to the manipulative procedure described above. t

diethylaminoethylcyclopentane-1,3-dione, treat a mixture of l-diethylamino 6(3,4-dimethoxyphenyl)hexan-3-one and 6-(3,4-dimethoxyphenyl)hex-l-en-3-one with 2-diethylaminoethylcyclopentane-1,3-dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2-[6-(3,5-dimethoxyphenyl)-3-oxohepty1]- 2dimethylaminopropylcyclopentane 1,3 dione, treat a mixture of l-diethylamino-6-(3,5-dimethoxyphenyl)hep tan 3 one and 6(3,5-dirnethoxyphenyl)hept-1-en-3-one with 2-dimethylaminopropylcyclopentane-1,3-dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2-[6-(3,5-diethoxyphenyl)-3-oxooctyl]-2-nbutyl-cyclopentane-1,3-dione, treat a mixture of 1-diethylamino-6-(3,5-diethoxyphenyl)octan-3-one and 6-(3,5diethoxyphenyl)oct-l-en-3-one with 2- butylcyclopentane- 1,3-dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2-[6-(3-methoxy 4 ethoxyphenyl)3oxo hexyl]-2-n-propylcyclopentane-1,3-dione, treat a mixture of 1 diethylamino-6-(3-methoxy-4-ethoxyphenyl)hexan- 3-one and 6-(3-methoxy-4-ethoxyphenyl)-hex-1-en-3-one with 2-propylcyclopentane-1,l-dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2-(6-m-methoxyphenyl 3 oxohexyl)2n propylcyclopentane-l,3-dione, treat a mixture of 1-diethylamino-6-m-methoxyphenyl hexan 3 one and 6-m-methoxyphenylhex-1-en-3-one with 2- propylcyclopentanev1,3-dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2-(-m-acetoxyphenyl-3-oxohexyl)-2-ethylcyc1opentane-1,3dione, treat a mixture of 1-diethylamino- 6-m-acetoxyphenyl-hexan-3-one and 6-m-acetoxyphenylheX-l-en-3-one with 2-ethylcyclopentane 1,3 dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

To prepare 2-(-m-hydroxyphenyl-3-oxohexy1)2-etliyl eyclopentane1,3dione, treat a mixture of l-diethylamino- -m-hydroxyphenyl-hexan-3-one and 6-m-hydroxyphenylhex-1-en-3-one with 2-ethylcyclopentane-1,3-dione and dry methanolic potassium hydroxide solution according to the manipulative procedure described above.

Example 31.-2-(6-m-methoxyphenyl-S-oxohexyl)- 2-mctlzylcyclopentane-I ,3-di0ne Add the crude methiodide of l-diethylamino--m-methoxyphenyl-hexan-S-one (2.5) g.) in methanol (10 cc.) ice-cold to a solution obtained by adding Z-methylcyclopentane-1,3dione (0.5 g.) to an ice-cold solution of sodium (0.21 g.) in methanol (10 cc.). Allow the reaction mixture to warm to room temperature and leave Yfor 16 hours, after which add N hydrochloric acid (10 cc.), and saturated brine cc.), and ether-extract the solution. Evaporate the Washed and dried extracts to obtain the crude adduct 2-(-m-methoxyphenyl-3-oxohexyl)-Z-methylcyclopentane-1,3-dione as a gum.

VThis compound is useful as an intermediate for preparing tlie novel compositions of this invention having hormonal activity.

Reiiux 6-m-methoxyphenylhex-l-en-3one, containing a small amount of 1-diethylamino-6-m-methoxyphenylhexan-3-one (6 g., the material produced by the slow distillation of the latter substance), with Z-methylcyclopentane-1,3dione (3.5 g.) in 0.12% anhydrous methanol in potassium hydroxide (10 cc.) for 10 hours.' Work up Found:

Add sodium (0.05 g.) to a 0.12% methanolic potassium hydroxide solution (15 cc.). To this solution add 1-bromo-6-(m-methoxyphenyl)hexan-3-one (0.9l g.) in methanol cc.) and Z-methylcyclopentane-1,3-dione (0.4 g.), and reflux the mixture for 6 hours. After Working up as in the preparation of the title compound in a previous example, obtain the crude Michael adduct 2- (-m-methoxyphenyl 3 oxohexyl) 2 methylcyclopentane-1,3-dione as a yellow gum.

This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

Reflux 2-ethylcyclohexane-1,3-dione (30.6 g.), pyridine (20 cc.), benzene (372 cc.) and a mixture of 1- diethylamino-6-mmethoxyphenylhexan3 one and 6 -mmethoxyphenylhex-l-en-3-one (40.3 g., produced by the distillation of the former substance) for hours. Wash the cooled reaction mixture with water, 10% aqueous sulfuric acid, Water, 10% aqueous sodium carbonate, Water, and brine, and lter. Evaporate the solvent to leave as residue 2-(-m-methoxyphenyl-3-oxohexyl)-2- ethylcyclohexane-1,3-dione (38.1 g.), 56.2%.

This compound is useful as an intermediate for the preparation of the novel compositions of this invention Which have hormonal activity.

Condense a mixture (6 g.) of 1-diethylamino-6-(m methoxyphenyl)-hexan-3-one and 6-(111-methoxyphenyl) heX-1en-3one with 2-isopropylcyclopentane-1,3-dione (3 g.) using a procedure similar to that described for the condensation of the Z-et-hyl compound. Obtain the corresponding triketone, 2-isopropyl-2-(6-m-methoxyphenyl- 3-oxohexyl)cyclopentane1,3dione (7.2 g.) as an uncrystallizable gum.

This compound is useful as an intermediate for the preparation of the novel compositionsof this invention which have hormonal activity.

Example 37.--2- (6-m-methoxyphenyl-S-oxohexyl) -2- sobutyl-l ,3-cyclopentanedione Reflux -m-methoxyphenylhex-l-en-3-one (126.9 g.)

20 with 2-isobutyl-1,3-cyclopentanedione (108 g.) in 0.12% methanolic potassium hydroxide solution for 20 hours. After removing the solvent in vacuo, dissolve the residue in a mixture of benzene-ether (1:1, 600 cc.) and filter the solution. Wash the ltrate successively with sulfuric acid, sodium bicarbonate, and Water, and dry. Evaporate the solvents to obtain 2-(6-m-methoxyphenyl-3- oxohexyl)2isobutyl 1,3 cyclopentanedione (154.9 g., 69.6%) as a gum.

This compound is useful as an termediate for the preparation of the novel compositions of this invention which have hormonal activity.

Reflux a mixture of 2-cetyl-1,3-cyclopentanedione (10.1 g.), m-methoxyphenylhex-1en3one (6.0 g.) and 0.02% methanolic potassium hydroxide solution cc.) for 26 hours and then cool. Dissolve the residue obtained after removal of solvent under reduced pressure in a mixture of benzene (50 cc.) and ether (50 cc.), and Wash the solution in turn with sodium carbonate solution, 10% aqueous sulfuric acid and Water. Remove the solvent by evaporation under reduced pressure to obtain as residue crude 2-cetyl-2-(6-m-methoxyphenyl-3-oxohexyl)l,3 cyclopentanedione (11.4 g.)

This compound is useful as an intermediate for the preparation of the novel compositions of this invention which have hormonal activity.

Reflux `a mixture of 6-(mrnethoxyphenyl)hept-l-en- 3-one andl-diethylamino-6-(m-methoxyphenyl)heptan-3- one (10 g., obtained by solW distillation of the latter substance) with Z-ethylcyolopentane-l,3-dione (7 g.) in 0.12% methanolic potassium hydroxide solution (40 cc.) for 15 hours. Remove most of the methanol under reduced pressure and add a mixture of equal volumes of et-her and benzene (50 cc.). Wash the solution with 5% aqueous sodium hydroxide, Water, 10% hydrochloric acid, and brine, and dry. Evaporate the solvent to leave as residue the triketone adduct 2-(6-m-methoxyphenyl-3- oxoheptyl)-2-ethylcyclopentane-1,3-dione (14 g.); infrared adsorption peak at 5.80p.

The compound is useful as an intermediate for the preparation of the novel compositions of this invention which have hormonal activity.

Add a mixture of 1-diethylamino6(m-rnethoxyphenyl)-S-methyl-hexan-3-one and 5 methyl 6 (rnmethoxyphenyl)hex1-en3one (6 g., prepared by slow distillation of the former substance) to 2-ethylcyclo pentane-1,3dione (3.5 g.) in 0.12% methanolic potassium hydroxide (10 cc.) and heat the mixtureV under redux for 16 hours. Remove most of the solvent under reduced pressure and add ether (25 cc.) and benzene (25 cc.) to the residue. Wash the solution with 5% aqueous sodium hydroxide, Water, dilute hydrochloric acid, and brine, and dry. Evaporate the solvent to obtain a viscous brown gum, which is thel triketone Z-ethyl- 2(6mmethoxyphenyl-5fmethyl 3 oxohexyl)cyclopentane-1,3-dione.

This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

Example 41.-42-(zi-phenyl-.-oxohexyl)-2- methylcyclohexane-I -lione ReuX the mixture of l-diethylarnino-6-phenylhexan- 3-one and 6phenylhex1-en3one(19 g.) with Z-methylcyclohexane-1,3dioue (8.4 g.) in benzene (97 cc.) containing pyridine (7.4 cc.) for 15 hours. Wash and dry aaoaese paring the novel compositions of this invention having hormonal activity.

Example 42.-,2-(6-pte1zyl-3-oxohexyl)-Z-methylcyclopentane-I ,3-done Reilux a mixture of crude 6-phenylhex-1-en-3-one (3.3 g., obtained by slow distillation of the ketoamine l-diethylamino-6-phenylhexan3-one) 2-methylcyclopentane-1,3- dione (1.5 g.), and 0.12% anhydrous methanolic potassum hydroxide (5.8 cc.) for 5 hour-s. Remove the solvent under reduced pressure and treat the residue with Water. Extract with ether. Evaporate the washed and dried ether extracts, leaving the crude triketone 2-(6- phenyl-3-oxohexyl)2 methylcyclopentane 1,3-dione (6 g.) as a reddish yellow gum; infrared absorption peaks at 2.86, 3.40, 5.81, 16.39p, indicating the presence of some aldol form in equilibrium with triketone.

This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

yExam ple 43 .-2 (6 -m-ntrophenyl- -oxohexyl -2-metltylcyclopentane-I ,3 -d ione 6-m-nitrophenylhex-1-en-3-one (1.0 g., containing a small amount of 1-diethylamino--m-nitrophenylhexan-3 one) in anhydrous 0.1% methanolic potassium hydroxide (10 cc.) with 2-"nethylcyclopentane-1,3-dione (1.5 g.) for 12 hours. Cool this solution, pour into water and etherextract. Wash the extracts with sodium bicarbonate solution, dry and evaporate to obtain a gum (1.3 g.). Crystallize by adding ethanol, recrystallize from ethanol to obtain 2 (6-m-nitrophenyl-3-oxohexyl) Z-methylcyclopentane-1,3-dione, M.P. 81-83 C.; infrared absorption peaks at 5.70, 5.80, 6.54, 7 .33a (the rst three peaks representing carbonyl groups and the others a nitro group).

This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

methylcyclopentane-l ,3-done Hydrogenate 2-(6-m-nitrophenyl-3-oxohexyl)-2-methylcyclopentane-1,3dione (0.165 g.) in ethanol (30 cc.) at atmospheric pressure using 10% palladized charcoal (0.1 g.) as catalyst. Hydrogenation will cease when hy drogen (39 cc.) equivalent to 3.2 molecular equivalents have been adsorbed. Filter and evaporate to obtain as residue ya gum; infrared absorption peaks at 2.88, 2.90, 5.83, 6.21, 12.74, 14.29a, indicating the product to be 2-(6-m-aminophenyl 3 oxohexyl)-rnethylcyclopentane- 1,3-dione, the corresponding triketone in which the nitro group has been reduced to a free amino group.

This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

Example 45 .-2- (-m-acetamdopltenyl-3-ox0hexyl -2- methylcyclopentane-I ,3-done Mix 2- (6-m-aminophenyl3oxohexyl)-2-methy1cyclopentane-1,3dione with acetic anhydride (0.25 cc.) and pyridine (3 cc.) and allow to stand overnight. Add ethanol to convert excess anhydride to ethyl acetate and remove all solvent under reduced pressure to obtain as .a gum 2-(6-m-acetamidophenyl-3-oxohexyl)-Z-methylcyclopentane- 1,3 -dione. Infrared absorption peaks at (liquid film) 2.98-3.03/.t (hydrogen bonded NH); 5.88p carbonyl in pentane ring); 5.87,a (acylic carbonyl); 5.95 and 6.43p. (two amide bands); 6.25, 12.74, and 14.29p (disubstituted aromatic nucleus).

This compound is useful as an intermediate for pre- Y 2S paring the novel compositions of this invention having hormonal activity.

Example 46.-2(6-m-hydroxyphenyl-.-oxohexyl)-2- methylcyclopentane-I ,S-dione Reflux 1-diethylamino-6-m-hydroxyphenylhexan-3-one (0.72 g.) with 2-methylcyclopentane-1,3-dione (0.70 g.) in 0.12% methanolic potassium hydroxide (5 cc.) for 18 hours. Remove the solvent under reduced pressure. Add chloroform (50 cc.) and wash the solution in turn with dilute sulfuric acid, saturated aqueous potassium bicarbonate, and brine, dry and evaporate the solvent. The product, an amber gum, is the adduct 2-(6-m-hydroxyphenyl-3-oxohexyl) 2 methylcyclopentane 1,3- dione. Infrared absorption peaks at 2.94, 5.71, 5.83 and 5.87p. This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

Redux a mixture of -(m-acetoxyphenyl)-l-diethylaminohexan-S-one and 6-(m-acetoxyphenyl)hex1en3 one (l g.), with 2-methylcyclopentane-1,3-dione (1.5 g.) in 0.12% methanolic potassium hydroxide (6 cc.) for 18 hours. Remove methanol (2 cc.) under reduced pressure and add chloroform (60 cc.). Wash the solution in turn with dilute sulfuric acid (25 ce), saturated potassium bicarbonate solution, and brine; dry and evaporate the solvent. The product (0.8 g.) is the adduct 2-(6-macetoxyphenyl 3 oxohexyl)-2-methylcyclopentane-1,3- dione in admixture with some of the corresponding free phenol; infrared absorption: 2.86 to 3.08 (broad 10W- intensity band), 5.71, 5.81, 5.85, and 8.25p.

This compound is useful as an intermediate for preparing the novel `compositions of this invention havin-g hormonal activity.

Example 48.-2 6-m-hydroxphenyl-3-oxolzexyl) -2-npropylcyclopentane-1,3-dione Heat together 2-n-propylcyclopentane-1,3-dione (13 g.), 1diethylamino-6-m-hydroxyphenylhexan-3-one and 0.12% methanolic potassium hydroxide solution (38 cc.) under gentle reiiux for 12 hours. Isolate the product to obtain the Michael adduct, 2(6-m-hydroxyphenyl-3 oxohexyl)-2-n-propylcyclopentane-1,3-dione as a brown gum (7.18 g.).

This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

Example 49,-2- [6- (3,4-dimeth0xypl1enyl) -3- oxohexyl] -2-ethylcycl0pentane-I ,3-dz0ne Reflux 6(3,4dimethoxyphenyl)hex-l-en 3 one, containing a small amount of 6-(3,4dimethoxyphenyl)-1-diethylaminohexan-3-one (6 g., produced by slow distillation of the latter substance) with 2-ethylcyclopentane-1, 3-dione (3.5 g.) in 0.12% anhydrous methanolic potassium hydroxide (10 cc.) for 10 hours. Remove most of the methanol under reduced pressure, add benzene (25 cc.) and ether (25 cc.) and wash the solution with water, dilute aqueous potassium hydroxide, dilute hydrochloric acid and water. Dry and evaporate the solvent to give the triketone adduct 2-[6-(3,4-dimethoxyphenyl)3oxo hexyl]-2-ethylcyclopentane-1,3-dione; infrared absorption (gum) 5.80, 6.25/1. (split peak).

This compound is useful as an intermediate for preparing the novel compositions of this invention having hormonal activity.

Reflux 6-(3,S-dimethoxyphenyl)hex-l-en-S-one, containing a small amount of 6-(3,5-dimeth0xyphenyl)1 diethylamnohexan-3-one (6 g., produced by slow distillation of the latter substance) with 2-ethylcyclopentane- (bath temperature 210, 0.5 .mm.).

paring the .novel compositions ofthis invention having hormonal activity.

Stir a mixture of diethyl 2-rnethyl-3-oxoadipate `(2.3 g., Bl. 111-112 C./0.2 min), prepared from Z-methylace-toa-cetic ester and ethoxycarbonylpropionyl chloride by the method of Cardwell, l. Chem. Soc., 1949, 715, and the methiodide of 1-rdiethylamino-6-m-methoxyphenylhexan-3-one (4.6 g.) in benzene (20 cc.) in an ice bath and add a solution of potassium (0.4 g.) in ethanol (10 cc.) dropwise over 1 hour. After stirring for a further 4 hours add ether (50 cc.) and evaporate the washed and dried ether extracts. Heat the residue at 160 C. and 0.2 mm. pressure to remove unchanged startingmaterials. The residual gum is diethyl l2(6-m-rnethoxyphenyl-Fi- Ioxohexyl)-Z-methyl-S-oxoadipate (2.7 g.);`infrared absorption peaks at 5.78, 5.88, 6.25, 12.82, 14.49/i.

vparing the novel compositions of this invention which have hormonal activity.

Example 5 2 -1 3 -methyl--mezhoxy-D-homogona-l ,3 ,5 (1 0) ,8,14-pentaen-l 7er-012e Reilux the dicyclic triketone 2-(6-m-methoxyphenyl-3- oxohexyl)-2-methylcyclohexane-1,3-dione (2 g.) for 2 hours in benzene (35 ce.) containing anhydrous toluenep-sulfonicacid (il g.) using a Dean-Stark trap to remove the water formed. The worked-up product is a solid which one recrystallizes from light petroleum (BP. 60- 80) and from vmethanol to give the pentaene `13-rnethyl- 3-methoxy-D-homogona `1,3,5 (10),8,14 pentaene 17aone (0.5 g.), MJ?. 13S-137 C.; ultraviolet absorption peak at 310 ma (e 30,000).

Cnil-12202 Calculated: C, 81.6%; C,8l.45%;H,7.7%. ,l l

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compound of this invention.

Example 53 .-eB-mehyl--methoxygona-l ,3,5(1 0) ,8,14-

H, 7.5%. Found;

Dissolve Ithe triketone 2-(6-mmethoxyphenyl3oxo hexyl)-Z-methylcyclopentane-1,3-diene (6.7 g.), in dry benaene 100 cc.) containing anhydrous toluene-p-sulfonic .acid (2.4 g.). Reiiux the mixture using a Dean-Stark water separator until the equivalent of two molecular proportions of water (0.99 cc.) is collected (30'minutes), indicating a double cyclo-dehydration. Cool and wash to remove acid, and dry.y Evaporate the dried solution to obtain .a redgum. Distil the gum under reduced pressure Recrystall-ize the solidified distillate from methanol, giving-13-methyl-3- methoxygona-l,3,5(),8,14-pentaen-17-one (3.9 g), Ml). 11S-116; ultraviolet absorption peak at 3,13 ma (e 35,100). The light absorption is in agreement with the structure assigned. v {215)}120()2 Calulated: C, H, 7.2%?. C, 81.1%; H, 7.0%. Y f

This compound has estrogenic activity, lowers the blood lipid level, `and is useful as an intermediate for preparing the hormonal compound of thislinvention,

` Found:

`Add` the crude methiodide of l-diethylamino-G-m-me- Y 30 thoxyphenylhexan-3-one (2.5 g.) in methanol (10 cc.) ice-cold to la solution obtained by adding Z-methylcyclopentane-1,3-dione (0.5 g.) to an ice-cold Vsolution of sodium (0.21 g.) in methanol (10 cc.).` Allow the reaction mixture to warm to room temperature and leave for 16 hours, after which ladd N hydrochloric acid (10 cc.) and saturated brine (100 cc.), ether-extracting the solution. Evaporate the washed and dried extracts t0 obtain crude 2-(6-rn-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione as a gum; dissolve in benzene (25 cc.) containing .toluene-p-sulfonic acid (0.4 g.) and rerlux the mixture for 1 hour. Cool, add ether ('25 cc.), and wash, dry, and evaporate the solution. Take up the resulting gum in benzene (5 cc.) and adsorb on a column of fullers earth (100 g). Elute with a mixture of benzene and light petroleum to obtain a series of fractions,`one of which crystallizes (0.04 g.). Boil this fraction with methanol and decant the Vsolution from insoluble oil which forms. Reduce the solution in bulk byev-aporation, depositing crystals on cooling: recrystallize from` methanol to obtain V13methyl3-rrreth0xygona-1,3,5 10) 8,14-pentaen-17-one, MP. 111w113 C.; ultraviolet ablsorp-tion peak at 312 ma (e 34,800).

This lcompound :has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds `of this invention.

VExample 55.-13-methyl-3-meth0xygona-1,3,5(10) 8,14-pe1`ctaen-1 7-0ne To 2- G-m-methoxyphenyl-S-oxohexyU -Z-methylcyclopentane-1,3dione (3 g.) in benzene (100 cc.), polyphosphoric acid (from orthophosphoric acid, 15 g., and phosphorus pentoxide, 6 g.) and heat the mixture at 90 for 4 minutes under such reduced pressure as the need to control frothing will allow. Cool, add water, and extract the mixture with ether and ethyl acetate; isolate the product from the resulting solution to vobtain the colorless crystalline 13e methyl 3 rnethoxygona 1,3,5(10r),8,14 pentaen-17-one (2 g.), MJ?. 11S-116; ultraviolet absorption peak at 313 ma (te 35,100).

To prepare 13,8-(3-hydroxypropyl)-3-methoxygona-1,3, 5(10),8,14-pentaen-17-one treat 2-(6-m-methoxyphenyl- 3 oxohexyl) 2 (3 hydroxypropyl)cyclopentane 1,3- dione with `polyphosphoric acid', according to themanipulative procedure described above.

To prepare 13-phenethyl-3-propoxygona-1,3,5(10),8, 14-pentaen-17-one -treat 2-(6-m-propoxyphenyl-3-oxohexyl) 2 phenethylcyclopentane 1,3 `dione with polyphosphoric acid according to the manipulative procedure described above.

To prepare 13-isobutyl-3-pentyloxygona-1,3,5(10),8, 14-pe'ntaen- 1 7- one Ytreat 2- (6-m-pentyloxyphenyl-3-oxohexyl)-2-isobutylcyclopentane-1,3-dionef with ,polyphosphoric acid according to the manipulative procedure described above.

To prepare 13,8-(3-hydroxypropy1)3cyclopentyloxygona-1,3,5(10),8,14-pentaen-17-one treat 2-(6-m-cyclopentyloxyphenyl 3 oxohexyl) 2-(3 hydroXypropyD- cyclopentene-1,3dione with polyphosphoric acid according to the 'manipulative proceduredescribed above.

To prepare 13 ,B-phenethyl-S-hydroxygona-1,3 ,5 10),8,

,14-pentaen-17-cne `tre at- 2- G-m-hydroxyphenyl-li-oxohex- [6 (3,5 dimethoxyphenyl) 3 oxoheptyl] 2(3 dj methylarninopropyl)cyclopentane 1,3` dione with poly- Example 56.-]3-methyl-S-methoxygona-I,3,5(10) 8,14-pentaen-17-one Heat the tricyclic diketone 5,6,7,8 tetrahydro 4-mmethoxyphenethyl 8methylindane-1,5dione (0.25 g.), Yunder nitrogen at 60 with a mixture of orthophosphoric Vacid (5 cc., sp. gr. 1.8) and phosphorus pentoxide (3.25 g.) for 20 minutes. Work up by means of ether to obtain a partially crystalline product which one takes up in benzene cc.) and filters. Recrystallize the residue to obtain the diene 13,6-methyl-3-methoxygona-l,3,5(l0), 8,14-pentaen-17-one (0.6 g.), M P. 11G-112 C.; ultraviolet absorption peaks at 310 ma (e 37,200); infrared absorption peak at 5.78a. g 'l This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing :the hormonal compounds of this invention.

Add 2-(6 m-methoxyphenyl-3-oxohexyl)-2-ethylcyclohexane-1,3-dione (32.8 g.) in benzene (400 ce.) to polyphosphoric acid (150 g.) in an atmosphere of nitrogen Vand stir the mixture at 60 for 3 hours. Add water, separate thevbenzene layer and wash with water until neutral. Dry the solution, remove the solvent, and recrystallize the residue from ethanol to obtain 13,8-ethyl-3- methoxy D homogona-1,3,5(10),8,14-pentaen-l7a-one, -M.P. 90-92; ultraviolet absorption peak at 311 my.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 58.-]3/8-etl1yl-3-metl10xyg0na-1,3,5 (10) 8,14-pentaen-1 7 -one Reflux the triketone 2ethyl2(6-m-methoxyphenyl-3- loxohexyl)cyclopentane-1,3dione (7.1 g.), in benzene 150 cc.) and toluene-p-sulfonic acid (2 g.) until the theoretical amount of water (0.72 cc.) for double cyclodehydration has been collected in a Dean-Stark separator. Wash the cooled reaction mixture after removal of solvent under reduced pressure, B.P. ca. 220/0.01 mm., to obtain an almost colorless glass (5.7 g.). Crystallize the glass from methanol containing a little ethyl acetate to obtain pure 13-ethyl 3 methoxygona-1,3,5(10),8,14 pentaen-17-one (3.7 g.), M.P. 77*80; ultraviolet absorption peak at 311 mp. (e 28,000).

C20H22O2 Calculated: C, 81.6%; H, 7.5%.V Found: C, 81.3%; H, 7.3%.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonalV compounds of this invention.

Example 59.-13-pr0pyl-3-metl10xyg0na-l,3,5 (10 8,14-pentaen-1 7-0ne Condense 2-propylcyclopentane-1,3-dione (13.1 g.) in '0.12% methanolic potassium hydroxide solution (90 cc.) with 6-m-methoxy-phenylhex-1-en-3-one (19.0 g), to obtain crude 2npropyl2(6-m-methoxyphenyl-3-oxohexyl) cyclopentane1,3dione (25.5 g.). Submit this Michael `condensation product (23.4 g.) to double cyclohydration rby heating with toluene-p-sulfonic acid, and distil the product at 200/ 10-4 mm.; crystallize the distillate from Vethanol to obtain the tetracyclic ketone 13-propyl-3- methoxygona-1,3,5(10),8,14pentaenl7one, M P. 82-84; ultraviolet absorption peak at 310 mp. (e 24,700).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Y Example 60,-3-methOxy-13-propyl-Dhomog0na- 1,3,5(10),8,14-pentaen-17a-one Cyclodehyrate 43 g. 2(6-m-methoxyphenyl-3-oxohexyl)2propylcyclohexane1,3-dione with polyphosphoric acid to obtain the title product (27.6 g.), M.P. 86-89, upon recrystallization from ethanol; ultraviolet 312 mp.

Calculated: C, 81.95%; H, 8.13%. Found: C, 82.11%;H,8.18%.

Reux the triketone 2-isopropyl-2-(6-m-methoxyphenyl- 3-oxohexyl)cyc1opentane1,3dione (7.2 g.) in benzene 150 cc.) and toluene-p-sulfonic acid (2.0 g.) until the theoretical amount of water (0.72 cc.) for double cyclodehydration has been collected in a Dean-Stark trap. Wash the cooled reaction mixture to remove acid and dry. Remove the solvent to obtain a gum. Distil the gum to obtain a glass (5 g.), which one crystallizes from methanol to obtain pure l3-isopropyl-3-methoxygona- 1,3,5(10),8,14pentaen17one (4.5 g.), Ml. 112-113.

C21H24O2 Calculated: C, 81.8%; H, 7.8%. Found: C, 8.8%; H, 7.6%.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Condense 2-n-butylcyclopentane-1,3-dione (2.8 g.) in 0.12% methanolic potassium hydroxide solution (8 cc.) with 6-mmethoxyphenylhex-1-en-3-one (5 g.) by heating the mixture at for 10 hours. Evaporate the solvent under reduced pressure and heat the residue with toluene-p-sulfonic acid (2 g.) in benzene (50 cc.) for 45 minutes using a Dean-Stark trap to effect double cyclodehydration. Add ether to the cooled reaction mixture, and evaporate the washed and dried ether solution; recrystallize the residue from ethanol to obtain 13-butyl-3-methoxygona-1,3,5(10),8,14pentaen17one (1.9 g), MP. 53-55 ultraviolet absorption peak at 312 ma (e 29,200).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Reflux a mixture of crude 2-(6-m-methoxyphenyl-3- oxohexyl)2isobutyl 1,3 cyclopentanedione (154.9 g.) and anhydrous p-toluenesulfonic acid 177 g.) in 5.2 liters of dry benzene for 3 hours using a Dean-Stark water separator. After cooling, filter the solution, wash, dry, and concentrate to 1/3 of its volume. Then lter through charcoal (Darco, 310 g.). Distil the ltrate to obtain a viscous oil, B P. 203 (bath temperature)/0.01 mm. RecrystalliZe from methanol-acetone to get 13isobutyl3meth oxygona-1,3,5(10),8,14pentaen17one, M.P. 57-60; ultraviolet absorption peak at 312 ma (e 25,200).

C22H26O2 Calculated: C, 81.9%; H, 8.1%. Found: C, 81.6%; H, 8.1%.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 64 .-v-I 3 -isopenty l-3-m ethoxy gona- 1,3,5 (),8,14-pentaen-17-one Cyclodehydrate 2 isopentyl-Z-(6-m-methoxyphenyl-3- oxohexyl)-cyclopentane-1,3dione (50 g.) at room temperature with p-tfoluenesulfonic acid. After two distillations, there is obtained 15.8 g. (35%) of the title product; ultraviolet 315 ma (e 18,040).

C23H23O2 Calculated: C, 82.39%; H, 8.32%. Found: C, 82.12%; H, 8.14%.

Reux a mixture of 2-cetylcyclopentane-1,3-dione (10.1 g.), 6-m-meth0xyphenylhex-1-en-3-one (6.0 g.) and 0.02% methanolic potassium hydroxide solution (120 cc.) for 26 hours and then cool. Dissolve the residue obtained after removal of solvent under'reduced pressure in a mixture of benzene (50 cc.) and ether (50 cc.), and Wash the solution in turn with sodium carbonate solution, 10% aqueous sulfuric acid and water. Remove the solvent by evaporation under reduced pressure to obtain as residue crude 2-cetyl-2-(-m-methoxyphenyl-3-oxohexyl) 1,3-cyclopentanedione (11.4 g.).

Add a solution of this Michael condensate in dry benzene (80 cc.) to a mixture of anhydrous toluene-p-sulfonic acid (2.4 g. and dry benzene (80 cc.) and reflux the mixture for 1 hour, using a Dean-Stark Water separator, until the equivalent of 2 moles of Water (0.75 cc.) has been collected. Wash the cooled solution, dry, and remove the solvent, leaving a purple oil (10.2 g.) which one then distills at about 220/ 0.001 mm. Recrystallize the solidilied distillate from acetonitrile, to obtain 13-cetyl-3-methoxygona-1,3,5(10),8,14pentaen17one, M.P. 55-56 C.; ultraviolet absorption peak at 316 mp. (e 24,000).

C34H50O2 Calculated: C, 83.2%; H, 10.3%. Found: C, 83.3%, H, 10.3%.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Cyclize 60 g. 2-(6-m-methoxyphenyl-3-oxoheptyl)-2- methylcyclo-pentane-1,3-dione with p-toluenesulfonic acid in benzene. After distillation of the crude product, there was obtained 43 g. of a gum which was crystallized from methanol to give 23 g. of material, M.P. 75-90. Repeated crystallization finally gave 1l g. 6-methyl epimer, M.P. 112-115 The mother liquors of the first recrystallization aif-orded 200 mg. of the 6er-methyl epimer, M.P. 109-111".

Example 67.13-etzyl-3-meth0xy-6-methylg0na 1,3,5 (10 ,8,14-pentaen-1 7-one Hydrate 1-diethylamino-6mmethoxyphenylhept --2-yne and distill to obtain 6-m-methoxyphenylhept-l-en-3or1e. Condense this material with Z-ethylcyclopentane-1,3-dione and cyclize the resulting intermediate with p-toluenesulfonic acid to obtain the title product; ultraviolet 3.15 ma (e 21,000).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 68.l3-ethyl-3-methoxy-7-metlzylgona- 1,3,5 (l0) ,8,14-pentaen-1 7-0ne Stir a mixture of 0.5 g. p-toluenesulfonic acid and 1 g. 13-ethyl 3 methoxy-7-methyl-8,14-secogona-1,3,5 (10), 9(l1)-tetraene-14,17dione in 50 ml. benzene at room temperature for two hours. Cool, filter, Wash with water and brine, dry, and evaporate to obtain 0.8 g. of the title product; infrared 5.75p.; ultraviolet 236 ma (e 13,650), 313 my, (e 28,600).

This compound has estrogenic activity, lowers the blood ture, and evaporate.

34 lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Reflux 2-carbethoxymethyl-1,3-cyclohexanedione monohydrate (6.0 g.) in 50 ml. benzene, removing the water formed by means of a Dean-Stark head. Add 2.6 ml. pyridine and 5.25 g. 6-m-methoxypheny1hex-1-en-3-o11e and reflux for twenty hours. Work up in the conventional manner to yield 2-car7oethoxymethyl-2-(G-m-methoxyphenyl-3-oxohexyl)cyclohexane-1,3dione (6.1 g.); infrared 5.77, 589,0. Reux this compound (4 g.) in 200 ml. benzene for one and one-half hours with vigorous stirring in the'presence of 25 g. polyphosphoric acid. Decompose the black reaction mixture with water, and Wash the yellow benzene layer with water until neutral. Evaporate the solvent to obtain a dark red gum, which crystallizes on scratching. Recrystallize from ethanolether to obtain a bright yellow solid (1.5 Vg.), M.P. 15S-156; infrared 5.76, 5.84/i; ultraviolet 320 my. (e 27,000).

Example 70.-13-cabethoxy--melzoxygona-l ,3,5 (10) I 8,14-pentaene Treat 1 diethylamino-6-m-methoxyphenylhexan-3-one (8.4 g.) with excess methyl iodide, controlling the exothermic reaction by external cooling. Remove the excess methyl iodide under reduced pressure, wash the gummy product with a little ether, and dry at 16 mm. to give diethyl 6-m-methoxyphenyl-3-oxohexyl tri-methyl ammonium iodide (13.5 g.) which one stirs with Z-carbethoxycyclopentanone (4.68 g.) in benzene (100 cc.) at 0 and potassium ethoxide (from the metal 1.27 g.) in ethanol (20 cc.) added dropwise over 45 minutes to the stirred solution. Stir the mixture for 2 hours at 0 and then at 20 for 16 hours. Add ether and water and wash the organic layer with ice-cold aqueous 2 N sodium hydroxide (3x50 cc.), water, dilute hydrochloric acid, and brine and dry. Evaporate the solvent to give an oil (10.8 g.). Reflux an aliquot (1.5 g.) in benzene (50 cc.) with p-toluenesulfonic acid (1 g.) for 1 hour. Wash the cooled solution with Water, dry and evaporate to give a gum which one chromatographs on neutral alumina (50 g.). Elute with light petroleum-benzene (4:1) and (1:1) to obtain a series of crystalline fractions which one combines and recrystallizes `from methanol to give the title product (0.162 g.), M.P. 60-63; A maximum 313 mu (e 28,588); 1/ maximum 1720 cml- Exam ple 7] .--1S-hyaroxymethyI-S-methoxygona- 1,3,5(10),8,14pentae1te Treat 13 carbethoxy-3-methoxygona-l,3,5(10),8,14 pentaene (0.225 g.) in ether (15 cc.) with lithium aluminum hydride (0.25 g.). After 10 minutes, add ethanol and water dropwise to decompose excess reagent. Add Celite and anhydrous magnesium sulfate, lilter the mix- Recrystallize the residue from light petroleum containing a little ethanol to give the ,title product (0.108 g.), M.P. 107110, raised to lll-113 by further recrystallization; A maximum 312 my. (e 23,700); v maximum 3300, 1600, 1250, 1035 cml Example 72 .-13-lzydroxymethyl-3-metl10xygona-1,3,5 (10),8,14pentaene, p-tolaenesulfonate Treat 13 hydroxymethy1-3-methoxygona-1,3,5(1.0),8, 14-pentaene (0.112 g.) in pyridine (0.25 cc.) with ptoluenesulfonyl chloride (0.128 g.) and allow the mixture to stand at 20 for 16 hours. Add water and extract the mixture with chloroform. Wash the organic extract, dry, and evaporate. Recrystallize 4the residue from ethyl acetate-ethanol to give the title product (0.068 g.), M.P. 128-129 d.; A maximum 312 ma (624,000); u maximum 1600, 1170, 950, 840 cm1 35 C27H28O4S Calculated: C, 72.3%; H, 6.29%. Found: C, 72.0%; H, 6.55%.

Example 73.-1.3p-methyl-3-l1ydroxyg0na-l,3,5(10)8,14- penlaen-I 7-0rze Reflux 2 (6-m-hydroxyphenyl-3-oxohexyl)-Z-methylcyclopentane-1,3-dione (0.5 g.), the product of Michael condensation of 2-methylcyclopentane-1,3-dione with 6- m-hydroxyphenyl-1-diethylaminohexan-3one, for 50 minutes in benzene (30 cc.) containing toluene-p-sulfonic acid (0.3 g.) using a Dean-Stark trap. Add ether (80 cc.) to the cooled product and filter oif the resulting insoluble material. Wash the ethereal solution in turn with water, saturated aqueous potassium bicarbonate, and brine, and dry. The product is a deep green gum which one takes up in a small quantity of ether; precipitate the insoluble impurities by the addition of light petroleum and filter ott. Evaporate the resulting solution to obtain a crystalline residue, which one takes up in a mixture of benzene 10 cc.) and ether (2 cc.); adsorb the solution on an activated Fullers earth (10 g.). Elute with benzene to obtain 13-1nethyl-3-hydroxygona-1,3,5(10),8,14 pentaen-l7-one (0.19 g.), M.P. 225 (decomp.).

CmHmOZ Calculated: C, 81.2%; H, 6.8%. C, 80.7%; H, 7.0%.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Found:

Allow 2-(6-m-hydroxyphenyl 3 oxohexy1)2-methyl cyclopentane-1,3dione (0.8 g.) to stand for 90 minutes at room temperature in benzene (80 cc.) containing anhydrous toluene-p-sulfonic acid (5 g). Wash the product with water, followed by aqueous sodium bicarbonate solution, and dry. Remove the solvent by evaporation to obtain a deep green gum; ultraviolet absorption peak at 313 ma (613,000). When this gum is seeded it becomes solid. Take up the crude material in benzene (15 cc.) and adsorb the solution on an activated Fullers earth (30 g); elute with benzene to obtain pale yellow 13- methyl-3-hydroxygona-1,3,5(10),8,14pentaen 17 one (0.6 g.).

This compound has estrogenc activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Reiiux 2 (6 m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3dione (0.8 g., the product of Michael condensation of 2methylcyclopentanedione and a mixture of 6-m-aeetoxyphenyl-1diethylaminohexan3-one and 6- m-acetoxyphenylhex-1-en-3-one, and containing some of the corresponding free phenolic compound) in benzene cc.) with toluene-p-sulfonic acid (0.3 g.) for 50 minutes. On cooling add ether (50 cc.) and wash the mixture in turn with water, saturated aqueous potassium bicarbonate, and brine; dry over anhydrous magnesium sulfate. The residue after removal of solvent is a purple gum (0.6 g.), part of which can be induced to crystaliize. Dissolve a portion (0.45 g.) of this gum in benzene and adsorb on an activated Fullers earth (40 g); elute with benzene to obtain 13-methyl-3-hydroxygona-1,3,5(10), 8,14-pentaen-17-one, which one recrystallizes from diisopropyl ether, M.P. 22S-226; ultra-violet absorption peak at 312.5 mp. (623,000); infrared absorption peaks at 2.99m 5.81m and 8.00,@

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

. 36 Example 76 .-1 3 -m ethyl-3 -lzydroxygona-I ,3,5 (10) 8,14-pentaen-1 7-one Place 300 g. of Warm polyphosphoric acid in a one liter flask fitter with dropping funnel, stirrer and thermometer. Add crude 2-(6-m-hydroxyphenyl 3 oxohexyl)-2-methylcyclopcntane 1,3 dione Michael adduct (28.3 gn), dissolved by Warming in dry benzene cc.) dropwise with stirring during 45 minutes to the acid at 40-50. Stir the mixture for a further 45 minutes by which time it becomes a very deep red. Add crushed ice with vigorous stirring and extract the resulting mixture with ether (3X250 cc.). A small quantity of black tar remains insoluble in either phase. Wash the combined ethereal extracts with saturated KHCO3 and brine, and then dry (MgSOQ. Remove the solvent on the rotary evaporator (temperature not greater than 40) to obtain a bright yellow crystalline solid. Wash by decantation with cold 20% ethyl acetate 60-80 petroleum ether (20 cc.), filter and dry to obtain crude 13 -methyl-3-hydroxygona 1,3,5(10),8,14-pentaen17one (19.35 g., 77%), MJ?. 16C-162 (dec.); ultraviolet absorption peak at 312 ma (622,200).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing o the hormonal compounds of this invention.

Example 77.-13/3-metzyl-3-acetoxygona-1,3,5 (10 8,14-pentaen-1 7-011e Mix 13B-methyl 3 hydroxygona-1,3,5(10),8,14pentaen-17-one with pyridine (3 cc.) and acetic anhydride (1 cc.) and keep at room temperature for 4 hours. Add ethanol (1 cc.) and remove low-boiling material under reduced pressure (0.1 mm.) to leave a red gum which crystallizes from a mixture of ethyl acetate and light petroleum. Recrystallize from methanol to obtain crystals of 13,8-methyl-3-acetoxygona-1,3,5(10),8,14pentacn 17- one, melting partially at 161-166 with resolidication at about 220 and finally melting at 260-265 (decomp.); infrared absorption peaks at 5.75/1 and 8.27/1, with absence of an absorption band due to a hydroxy group; ultraviolet absorption peak at 307.5 mp. (624,000).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 78 .-1 3 -ethyl-j -lzydroxygona-I ,3,5 l 0 8,14-pentaen-1 7-o1ze Reflux 2-(6-m-hydroxyphenyl-3-oxohexyl) 2 ethylcyclopentane-1,3dione (2.6 g.) for 30 minutes in benzene (70 cc.) containing toluene-p-sulfonic acid (0.38 g), and collect the water evolved in the cyclodehydration in a Dean-Stark separator. Work up to obtain a green gum which one dissolves in benzene (30 ce); adsorb the benzene solution on a column of activated Fullers earth, and elute with benzene to obtain crude 13-ethyl-3-hydroxygona-1,3,5(l0),8,14pentaen17one (0.75 g.), as pale yellow crystals, MP. 153-156; ultraviolet absorption peak at 313.5 ma (630,300); infrared absorption peaks at 3.99,:1J and 5.81 a.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Allow 2 (6-m-hydroxyphenyl-3-oxohexyl) 2 ethylcyclopentane-1,3dione (8.8 g.) to stand 24 hours at room temperature in solution in benzene (430 cc.) containing 37 melting to a clear liquid on rapid heating; ultraviolet absorption peak at 314 my. (630,000).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the harmonal compounds of this invention.

Add 2 (6-m-hydroxyphenyl-3-oxohexyl),-Z-ethylcyclopentane-LS-diOne (28.3 g.) in benzene (70 cc.) during 45 minutes tol polyphosphoric acid (300 g., containing 80% phosphorous pentoxide) andmaintain at 40-5 0, with stirring. Stir the reaction mixture for a further 45 minutes during which it develops a deep red coloration. Add crushed ice and extract the product with ether. Evaporate the washed and dried extracts at a temperature not greater than 40 to obtain a bright yellow crystalline solid; wash by decantation with light petroleum containing a small proportion of ether.; filter and dry to obtain 1318- ethyl 3 hydroxygona 1,3,5(10),8,14 pentaen-17-one (19.35 g.), MP. l60-l62 7 ultraviolet absorption peak at 312 mp (622,200).

This compound has estrogenic activity, lowers the blood lipid level, and, is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 81.-13,3-kyle-hydroxygonaz,3,5(101.8,142

pen'men-U-oney Add a solution of 2-(6-rn-acetoxyphenyl-3-oxohexyl) 2-ethylcyclopentane-l,3-dione (18.0 g.) in benzene (40 cc.) during 1% hours to stirred poly/phosphoric acid (180 g., containing 80% phosphorous pentoxide) and maintain at 40-42. Keep the reaction mixture at this temperature for a. further hour with occasional stirring, add ice and water, and extract the product with ether. Evaporate the washed: and dried extracts under reduced pressure to obtain a crude solid product (13.4 g.), containing 13 -ethyLl 36hydroxygona-1,3,5(l0),8,14-pentaen-l7-one and its 3- acetate in a proportion indicated by spectroscopic analysisto be 7:3; ultraviolet absorption peak at 312 mp. (612,700).

This 3-hydroxy compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Dissolve 13-etl1yl-3-hydroxygona?1,3,5 10),8,14pen taenl7fone (2.45 g.) in pyridine (7 cc.) and acetic anhydride (4 cc.) Vand allow to stand at room temperature for 16 hours. Remove the solvent under reduced pressure, add ethanol (20 cc.) and again evaporate'the solvent. Recrystallize the residue from ethanol to give a red crystalline solid, M.P. 1224124. Filter the solidV through Florisil (10.0 g.) with benzene, evaporate the solvent and recrystallize the product from` ethanol to obtain 13,8-ethyl- 3-acetoxygona-1,3,5(10),8,l4pentaenl7one, Mzl.. 129- 130 C.;ultraviolet absorption peakrat 306 mp. (25,500), infrared absorption peaksat 5.78/2, 8.27p and 9.85/l.v

CMI-12203 Calculated: C, 78.25%; H, 6.9%. Found: C, 78.4% ;,H, 6.65%.

This compound has estrogenicractivity, lowers the blood lipid level, and is useful as an rintermediate for preparing the hormonal compounds of this invention.

l Example 83 .-1 3-ethylTS-hydroxygona-l ,3,5 (10 ,8,1.4 Y pentaen-17-one phosphate Treat 13`ethyl3hydroxygonal ,3,5 l0),8,l4epentaen 17-one in pyridine Wtih phosphonyl chloride at -l0 for one hour and work up conventionally to'obtain the title product. l Y

Cyclodehydrate 2- 6-m-hydroxyplienyl-3 -oxohexyl -2- 233 n-propylcyclopentane-1,3-dione (7.18 g.) by heating in benzene (210 cc.) containing toluene-psulfonic acid (0.75 g.), to obtain a deep green gum (6.4 g.); chromatograph in benzene on a Column of activated fullers earth, to give a yellow gum. Crystallize from ethanol, and then from a mixture of benzeneand light petroleum to obtain 13,6- propyl 3 hydroxygona-l,3,5(l0),8,l4pentaenl7one (0.59 g.), MP. 149-155 with some premelting at 13S- 138; ultraviolet absorption peak at 313 mp (627,000).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Dissolve 6.1 g. 6,7-dimethoxy-l-tetralone in 50 ml. tetrahydrofuran and add to 400 ml. of 2 moles vinyl magnesiurn chloride in tetrahydrofuran at room temperature. Let stand for 3-4 hours, and pour into saturated ammoni- V um chloride solution. Extract with ether, wash with water,

dry, and evaporate to obtain 1,2,3,4tetrahydro6,7di methoxy-1-vinyl-1-naphthol. Dissolve in 30 ml. methanol and add to 4 g. 2-methylcyclopentane-1,3-dione in 5 ml. methanol, containing a trace of potassium hydroxide. Re flux for 3 hours, cool, pour into water, and extract with ether. water, dry, and evaporate to obtain 2,3-dimethoxy-l3f methyl 8,14 secogona-1,3,5(l0),9(l1)-tetraene-l4,l7 dione. Recrystallize from methanol to obtain 5.45 g., MT. 10ft-106.

CRI-i240., Calculated: C, 73.12%; H, 7.37%. Found: C, 73.37%; l-l, 7.14%.

Dissolve l g. of this seco compound in 15 ml. refluxing methanol. While boiling, add conc. hydrochloric acid dropwise until the solution becomes turbid. Remove the turbidity with a few drops of tetrahydrofuran and boil for 5 minutes, after which time crystals appear. Cool, lter off the solid, wash with methanol, and recrystallize from ethanol to obtain 450 mg. of the title product, M.P. 137- C20H22O3 Calculated: C, 77.39%; H, 7.11%. Found: C, 77.17%; H, 7.05%.

Exam ple 86 .-1 3 -etlzyl-Z,3-dimethoxygona- 1,3,5 (10) ,8,Z4-pentaen-1 7-0118 Dissolve the crude triketone 2[6-(3,4dirnethoxy phenyl)3oxohexyl]-Z-ethylcyclopentane-l,3-dione (6.5 g.) in dry benzenel cc.) containing anhydrous toluene-p-sulfonic acid (2.4 g.) and retlux under a Dean- Stark water separator for 45 minutes. WashV the cooled solution with water, sodium carbonate solution, and water,

and dry. Evaporate the solvent and distil the red gummy residue at 220 (bath temperature) 0.01 mm. to give a yellow gum; recrystallize from methanol to obtain 13pethyl- 2,3 dimethoxygona 1,3,5 l0) ,8,14 pentaen 17- one; ultraviolet absorption peak at 314 mp (629,000); infrared absorption peaks at 5.84p and 8.00p.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

` Example 87.-31-ethyl1,3-dmet1oxyg0na-I,3,5 (10),

8,14-pentaen-17-one Y Using thetriketone 2- [6- 3,5 -dirnethoxyphenyD -3-oxohexyl]-Z-ethylcyclopentane-1,3dione (6.5 g.), proceed exactly as described in the preceding example to obtain 13ethyll,3 dimethoxygona l,3,5(10),8,l4pentae11 l7-one';` infrared absorption peaks at 5.74pV and 8.00p..

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for prepar- Y Dissolve 13 -ethyl3-hydroxygona1,3,5 10) ,8,14-pentaen-17-one (0.5 g.) in methanol (30 cc.) and add a Wash the extracts with sodium bicarbonate and 

5. A CHEMICAL COMPOUND HAVING THE GONA-1,3,5(10), 8,14-PENTAENE NUCLEUS, SAID NUCLEUS HAVING ATTACHED THERETO, IN THE 13-POSITION, A POLYCARBON-ALKYL RADICAL.
 9. 13B-METHYL - 3 - METHOXYGONA - 1,3,5(10),8,14-PENTAEN-17-ONE. 